Adenosine and ATP Receptors in the Brain - Ingenta Connect

Current Topics in Medicinal Chemistry, 2011, 11, 973-1011

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Adenosine and ATP Receptors in the Brain Geoffrey Burnstock1,*, Bertil B. Fredholm2 and Alexei Verkhratsky3,4 1

Autonomic Neuroscience Centre, University College Medical School, London, UK; 2Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 3Faculty of Life Sciences, The University of Manchester, Manchester, UK; 4Institute of Experimental Medicine, ASCR, Videnska 1083, 142 20 Prague 4, Czech Republic Abstract: There is a widespread presence of both adenosine (P1) and P2 nucleotide receptors in the brain on both neurones and glial cells. Adenosine receptors play a major role in presynaptic neuromodulation, while P2X receptors are involved in fast synaptic transmission and synaptic plasticity. P2Y receptors largely mediate presynaptic activities. Both P1 and P2 receptors participate in neurone-glia interactions. Purinergic signalling is involved in control of cerebral vascular tone and remodelling. Examples of the roles of purinoceptors in neuropathology involve: A2A receptors in Parkinson's disease and epilepsy, P2 receptors in trauma, ischaemia, neuroinflammatory and neuropsychiatric disorders, and neuropathic pain.

Keywords: Ischaemia, CNS, glia, neurones, neurodegeneration, neuropathology, purinergic transmission. INTRODUCTION: PURINERGIC TRANSMISSION The concept of purinergic neurotransmission was proposed in 1972 [1], after it was shown that adenosine 5’triphosphate (ATP) was a transmitter in non-adrenergic, noncholinergic inhibitory nerves in the guinea-pig taenia coli. Subsequently ATP was identified as a cotransmitter in sympathetic and parasympathetic nerves [2] and it is now recognised that ATP acts as a cotransmitter in most nerves in both the peripheral nervous system and central nervous system (CNS) [3-5]. Various purinergic receptor subtypes have been shown to be widely distributed throughout the CNS, being present in neurones and glia [4,6]. It is now well established that ATP acts both as a fast excitatory neurotransmitter or neuromodulator and has potent long-term (trophic) roles in cell proliferation, differentiation and death in development and regeneration, as well as in disease [7-9]. Purinergic receptors were first defined in 1976 [10] and 2 years later a basis for distinguishing two types of purinoceptor, classified as P1 and P2 (for adenosine and ATP/ adenosine diphosphate (ADP), respectively) was proposed [11]. At about the same time, two subtypes of the P1 (adenosine) receptor were recognised [12,13], but it was not until 1985 that a proposal suggesting a pharmacological basis for distinguishing two types of P2 receptor (P2X and P2Y) was made [14]. In 1994 Abbracchio and Burnstock [15], on the basis of studies of transduction mechanisms [16] and the cloning of nucleotide receptors [17-20] proposed that purinoceptors should belong to two major families: a P2X family of ligand-gated ion channel receptors and a P2Y family of G protein-coupled receptors. This nomenclature has been widely adopted and currently seven P2X subunits and eight P2Y receptor subtypes are recognised, including receptors that are sensitive to pyrimidines as well as purines (see [21]).

*Address correspondence to this author at the Autonomic Neuroscience Centre, University College Medical School, London, Rowland Hill Street, London NW3 2PF; UK; Tel: (+44) 20 7830 2948; Fax: (+44) 20 7830 2949; E-mail: [email protected]

1568-0266/11 $58.00+.00

There is compelling evidence for exocytotic neuronal vesicular release of ATP [22] and there is also support for vesicular release of ATP from astrocytes [23,24], perhaps involving lysosomes [25]. Evidence has been provided for additional mechanisms of nucleotide release, including ATPbinding cassette transporters, hemichannels, plasmalemmal voltage-dependent anion channels, and P2X7 receptors [2628]. After release, ATP and other nucleotides undergo rapid enzymatic degradation by ectonucleotidases, which is functionally important as ATP metabolites act as physiological ligands for various purinergic receptors [29]. Ectonucleotidases include the E-NTPDases (ecto-nucleoside triphosphate diphosphohydrolases), E-NPPs (ecto-nucleotide pyrophosphatase/phosphodiesterases), alkaline phosphatases and ecto5´-nucleotidase. Although generally adenosine is produced by ectoenzymatic breakdown of ATP, there may be subpopulations of neurones and/or astrocytes that release adenosine directly [30]. The actions of adenosine in the CNS have been recognised for many years (see [31-38]). However, consideration of the role(s) of ATP in the CNS received less attention until more recently see [5, 39-47]. In particular, fast purinergic synaptic transmission has been clearly identified in the brain [48, 49]. It was first identified in the medial habenula [50] and has been subsequently described in other areas of the CNS, including spinal cord [51], locus coeruleus [52], hippocampus [53,54] and somatic-sensory cortex [55, 56]. Electron microscopic immunocytochemical studies support these functional experiments. Although adenosine, following ectoenzymatic breakdown of ATP, is the predominant presynaptic modulator of transmitter release in the CNS (see [34]), ATP itself can also act presynaptically [57]. A strong case is made for coordinated purinergic regulatory systems in the CNS controlling local network behaviours by regulating the balance between the effects of ATP, adenosine and ectonucleotidases on synaptic transmission [58, 59]. ATP is present in high concentrations within the brain, varying from approximately 2 mM/Kg in the cortex to 4mM/Kg in the putamen and hippo© 2011 Bentham Science Publishers Ltd.

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campus [60]. Much is now known about the breakdown of ATP released in the CNS. Cortex and hippocampus synaptic membranes exhibit higher activities of NTPDase1 and NTPDase2 than cerebellum and medulla oblongata, while ecto-5'-nucleotidases and adenosine deaminase were found in most brain regions [61]. The adenosine receptor subtype dominant in the brain is A1, with its major action as a prejunctional modulator of excitatory transmitter release. Neuroprotective actions have been attributed to A2A receptor antagonists; A2B and A3 receptors have also been identified in the brain [37]. In situ hybridisation of P2 receptor subtype mRNA and immunohistochemistry of receptor subtype proteins have been carried out in recent years to show wide, but heterogeneous distribution in the CNS of both P2X receptors [62-65] and P2Y receptors [39,66,67]. The P2X2, P2X4 and P2X6 receptors are widespread in the brain and often form heteromultimers. P2X1 receptors are found in some regions such as cerebellum and P2X3 receptors in the brain stem. P2X7 receptors are probably largely pre-junctional. P2Y1 receptors are also abundant and widespread in the brain. The hippocampus expresses all P2X receptor subtypes and P2Y1, P2Y2, P2Y4, P2Y6 and P2Y12 receptors. Details of the distribution and roles of P1 and P2 receptor subtypes are described below. Evidence has been presented that nucleotides can act synergistically with growth factors to regulate trophic events [68,69]. However, a recent paper has shown that ATP can also stimulate neurite outgrowth from neuroblastoma cells independent of nerve growth factor [70]. Evidence for purinergic cotransmission in the CNS has lagged behind that presented for purinergic cotransmission in the periphery (see [71]). However, in the last few years a number of such studies have been reported. Release of ATP from synaptosomal preparations and slices from discrete areas of the rat and guinea-pig brain including cortex, hypothalamus, medulla and habenula, has been measured [72-74]. In cortical synaptosomes, a proportion of the ATP appears to be coreleased with acetylcholine (ACh), and a smaller proportion with noradrenaline (NA) [75]. In preparations of affinity-purified cholinergic nerve terminals from the rat caudate nucleus, ATP and ACh are coreleased [76]. There is evidence for corelease of ATP with catecholamines from neurones in the locus coeruleus [77] and hypothalamus [73, 78]. Purinergic and adrenergic agonist synergism for vasopressin and oxytocin release from hypothalamic supraoptic neurones is consistent with ATP cotransmission in the hypothalamus [79]. Corelease of ATP with -aminobutyric acid (GABA) has been demonstrated in the rabbit retina [80] and in dorsal horn and lateral hypothalamic neurones [81]. There is evidence for corelease of ATP with glutamate in the hippocampus [54] as well as widespread and pronounced modulatory effects of ATP on glutamatergic mechanisms [82]. A recent study has shown that in central neuronal terminals, ATP is primarily stored and released from a distinct pool of vesicles (which however share the presynaptic terminals with glutamate vesicles) and that the release of ATP is not synchronized either with the cotransmitters GABA or glutamate [22,23]. Cooperativity between extracellular ATP and N-methyl-D-aspartate (NMDA) receptors in long-term potentiation (LTP) induction in hippocampal CA1 neurones [83] is consistent with ATP/glutamate cotransmission. Colo-

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calisation of functional nicotinic and ionotropic nucleotide receptors has also been identified in isolated cholinergic synaptic terminals in midbrain [84]. Interactions between P2X2 and both 44 and 42 nicotinic receptor channels have been shown in oocyte expression studies [85]. There is indirect evidence supporting the possibility that dopamine and ATP are cotransmitters in the CNS [86]. A detailed account of the distribution of multiple P1 and P2 receptor subtypes expressed by astrocytes, oligodendrocytes and microglia is described in the following sections (see also [6,62]). Importantly, ATP acts as the major gliotransmitter, intimately involved in signalling in neuronalglial and glial-glial circuitry [87-89]. Adenosine stimulates glutamate release from astrocytes via A2A receptors [90]. A 3 receptors mediate chemokine CCL2 synthesis in cultured mouse astrocytes [91]. Astrocytes in the cortex and cerebellum express P2Y13 as well as P2Y1 and P2X2 receptors [92]. NTPDase2 is the dominant ectonucleotidase expressed by rat astrocytes [93]. ATP participates in both short-term calcium signalling events and in long-term proliferation, differentiation and death of glia [94]. Both adenosine and ATP induce astroglial cell proliferation and the formation of reactive astrogliosis [95]. Extracellular nucleotide signalling has also been identified in adult neural stem cells [96]. Release of ATP through connexin hemichannels in astrocytes has been reported [97], although vesicular release has also been described [98,99]. It has also been suggested that P2X7 receptor pores may directly mediate efflux of cytosolic ATP, glutamate and GABA from glial cells in the CNS [100]. Another study has shown that cultured astrocytes are able to release uridine 5’-triphosphate (UTP) either at rest or following hypoxia and that P2Y2 receptor mRNA increased by 2-fold during glucose-oxygen deprivation [101]. P2Y2 and P2Y4 receptors are strongly expressed in glial endfeet apposed to blood vessel walls [102,103]. Purinergic signalling is emerging as a major means of integrating functional activity between neurones, glial and vascular cells in the CNS. These interactions mediate effects of neural activity, in development and in association with neurodegeneration, myelination, inflammation and cancer (see [3,104-106]). This common currency for cell-cell communication opened the possibility of an intercellular signalling system that could unite glia and neurones functionally. While the involvement of purinergic signalling in neurotransmission and neuromodulation in the CNS is now well established, there are relatively few studies of the involvement of purinergic signalling in behavioural pathways, apart from brain stem control of autonomic functions, although behavioural changes have been reported in pathological situations (see [4]). ATP and adenosine are involved in mechanisms of synaptic plasticity and memory formation [107,108]. Adenosine, acting through A1 receptors, is an endogenous, homeostatic sleep factor, mediating the sleepiness that follows prolonged wakefulness [109]. ATP, probably acting via P2X7 receptors in glia to release cytokines, has also been implicated in sleep (see [110]). The central inhibitory effects of adenosine on locomotor activity of rodents and antagonism by caffeine have been known for some time (e.g. [111-113]). Adenosine given centrally can result in a decrease in food intake [114]. It has been reported that feed-

Purinoceptors in the Brain

ing behaviour relies on tonic activation of A2A receptors in the nucleus accumbens in rats [115]. Enhanced food intake after stimulation of hypothalamic P2Y1 receptors in rats has also been described [116]. Both adenosine and ATP have been implicated in mood and motivation behaviour [117,118]. There is a rapidly growing literature about the involvement of purinergic signalling in most disorders of the CNS, such as neurodegeneration diseases, including Alzheimer's, Parkinson's and Huntington's diseases and multiple sclerosis, cerebral ischaemia, migraine, neuropsychiatric and mood disorders (see [119]) and later Sections. ADENOSINE RECEPTORS IN NEURONES Adenosine receptors were well characterized and partially purified by the mid 1980’s. Nevertheless, the cloning of the first two adenosine receptors, A1 and A2A, was serendipitous and depended on a library of orphan receptors from the dog thyroid [120,121]. Soon the same receptors were cloned from rat and humans [122,123] and a related receptor, the A2B receptor, was cloned from rat brain [124]. These receptors had all been predicted pharmacologically. The fourth receptor, A3, was unexpected [125]. By now the four adenosine receptors have been cloned from several mammalian and non-mammalian species. A1, A2A and A2B receptors are well conserved among mammals, but A3 receptors show considerable structural variability. For all four adenosine receptors the coding region is split up by an intron in a region corresponding to the second intracellular loop [126]. All these receptors are G protein-coupled. After activation of the G proteins, enzymes and ion channels are affected as can be predicted from what is known about G protein signalling. Thus, A1 receptors mediate inhibition of adenylyl cyclase, activation of several types of K+ channels (probably via ,-subunits), inactivation of N, P and Q-type Ca2+ channels, activation of phospholipase C etc. The same appears to be true for A3 receptors [127]. Given that many of the steps in the signalling cascade involve signal amplification, it is not surprising that the position of the dose-response curve for agonists will depend on which particular effect is measured [128-130]. Both A2A and A2B receptors stimulate the formation of cyclic adenosine monophosphate (cAMP), but other actions, including mobilization of intracellular calcium (e.g. [131]), have also been described. The distribution of receptors tells us where administered agonists and antagonists could act. The rather low levels of endogenous adenosine present under basal physiological conditions have the potential of activating receptors where they are abundant, but not where they are sparse [132-135]. Adenosine A1 receptors are widely distributed in the brain of mammals, with particularly high levels being found in hippocampus and cerebellum [136-138]. In several regions of the CNS, receptor binding and expression of transcript do not exactly match [139] and the two are differently regulated by long-term antagonist treatment and during development [140]. Much of the differential distribution can be explained by the fact that many adenosine A1 receptors are present at nerve terminals (whereas the message is mostly in cell bodies). A similar explanation probably underlies the observations that A2A receptors are present in

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globus pallidum, despite the fact that A2A receptor mRNA cannot be detected there [135,141]. These receptors are probably located at the terminals of the striatopallidal GABAergic neurones [142-144]. Adenosine A2A receptor mRNA is highly enriched in the striatum [138,145,146]. Lower levels are also found in extrastriatal areas, such as lateral septum, cerebellum, cortex and hippocampus [138,147]. Most striatal neurones (95%) are GABAergic projection neurones. These neurones can be divided into two major subtypes, based on their target areas and neuropeptide contents. One sub-population projects to globus pallidus and contains enkephalin. Another subpopulation projects to substantia nigra pars reticulata/the entopeduncular nucleus and contains substance P and dynorphin. Interestingly, adenosine A2A receptors are selectively expressed in the enkephalin-containing striatopallidal neurones [138,145,146,148]. In addition to the GABAergic projection neurones, there are also cholinergic and GABAergic interneurones in striatum. It is still controversial whether these interneurones contain adenosine A2A receptors. Studies using in situ hybridization have been unable to detect adenosine A2A receptor mRNA in interneurones [138,146,148]. However, a single cell PCR study detected adenosine A2A receptor mRNA in cholinergic interneurones [149]. Studies using immunohistochemistry and ligand autoradiography show high levels of adenosine A2A receptors in all sub-regions of striatum [142,150,151]. Using A2A receptorselective antibodies and immunohistochemistry at the lightand electron-microscopic levels, Rosin and her colleagues [142,152] have shown that striatal adenosine A2A receptors are found in most neuronal compartments, i.e. dendrites, terminals of axon collaterals and in soma. However, the highest levels are found in dendrites and dendritic spines that form asymmetric synapses. These synapses receive input from glutamatergic terminals and are of an excitatory nature. This postsynaptic localization of A2A receptors implies that A2A receptors may play an important role in the regulation of synaptic plasticity. Indeed, a functional correlate to this anatomical finding has recently been demonstrated, namely that NMDA receptor-dependent LTP in the nucleus accumbens is significantly attenuated by selective A2A receptor antagonists or in A2A receptor knock out (KO) mice [153]. The distribution of adenosine A2A receptors is similar in rodents and humans [146,154]. However, the levels of extrastriatal adenosine A2A receptors appear to be higher in humans than in rodents. Since there is accumulating evidence for a critical role of adenosine A2A receptors in the pathophysiology of several neurological and psychiatric disorders, most notably Parkinson’s disease and schizophrenia, it will be of great interest to be able to monitor the levels of adenosine A2A receptors in the living brain using PET. There are several reports about various ligands, including [11C]KW-6002, [11C]IS-DMPX, [11C]KF 18446 and [11C]KF 17837 [155-157]. These PET ligands do not appear to be ideal since non-specific, extrastriatal binding is high. The recently developed A2A tracer, [11C]SCH442416, demonstrated high selectivity and good signal-to noise ratio in the in vivo imaging of these receptors in both rats and primates [158].


Biochemical studies have demonstrated low levels of adenosine A2B receptors on most neurones and glia cells and in situ hybridization studies specifically demonstrated the presence of adenosine A2B receptor mRNA in the hypophyseal pars tuberalis [124]. The levels of A3 receptors in the brain are also low, but there appear to be species differences, with the levels being higher in sheep and humans than in rodents [159,160]. The Close Relationship between A2A Receptors and Dopamine In 1974, Kjell Fuxe and Urban Ungerstedt showed that theophylline could by itself induce the same type of rotationbehaviour that was induced by drugs that directly or indirectly stimulated dopamine receptors and that it could markedly enhance dopamine-mediated effects [161]. The effect was interpreted as secondary to blockade of phosphodiesterase (PDE), but soon the potency of the drugs fitted much better with their potency as adenosine antagonists (or enhancers) than their potency as PDE inhibitors [162]. Together these studies showed that methylxanthines, probably by blocking adenosine receptors, could potentially be used as treatment in Parkinson’s disease, and highlighted a relation to dopamine. Studies, in two laboratories, of dopaminestimulated adenylyl cyclase in brain, also showed that methylxanthines could lower “basal” enzyme activity and that adenosine could stimulate it [163,164]. This was observed in dopamine-rich areas of the brain, including caudate-putamen and tuberculum olfactorium, but not in other brain areas. These results suggested that these parts of the brain might have a different set of adenosine receptors than other brain areas. This contention received support during the following decade as methods to study receptors using binding techniques were developed. The first studies used relatively nonselective radioligands but pharmacological means to discriminate between multiple binding sites [165-168]. Later studies used a selective ligand for A2A receptors, including CGS 21680, [169-171]. Thus, one adenosine receptor, the A2A receptor, is enriched in dopamine rich areas of the brain and this offers a rationale for examining the role of adenosine in mediating or modulating behaviours and traits traditionally associated with dopamine. The availability of more selective adenosine receptor agonists and antagonists also reinforced the idea that behavioural consequences of adenosine A2 and dopamine receptor-mediated effects tended to be opposite [172-176]. Using binding, it was found that high affinity binding of D2 agonists could be reduced by stimulation of adenosine A2A receptors [177]. This finding suggested that there were interactions directly between the receptors, an issue that has been forcefully pursued by Kjell Fuxe and his colleagues [178]. Using increasingly sophisticated methods it was proven that the bulk of A2A expression is confined to one set of neurones in the striatum, namely those GABAergic output neurones that constitute the so-called indirect pathway [139,141,145,146,179-181]. These cells also express the bulk of the dopamine D2 receptors. Hence, the link between A2A and dopamine D2 receptors was further strengthened.

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Stimulatory doses of caffeine and selective A2A receptor antagonists caused a decrease in the expression of immediate early genes (IEG), known to be regulated by the cAMP/cyclic AMP responsive element binding protein (CREB) cascade, in striatopallidal neurones [182,183]. These and subsequent studies [184-187] provide strong evidence that adenosine, via A2A receptors, exerts a robust tonic activation of the cAMP/CREB/IEG cascade in striatopallidal neurones. Moreover, this result also provided evidence that multiple D2 receptor-mediated effects by dopamine can be attributed to an antagonism of this adenosine-mediated activation of striatopallidal neurones. DARPP-32 is a phosphoprotein highly enriched in all striatal GABAergic medium-sized projection neurones and is an important mediator of dopaminergic signalling [188]. Its function is determined by its relative phosphorylation state at several different threonine/serine residues, of which the most studied is a PKA-site Thr34. It was found that CGS 21680 potently increases phosphorylation at Thr34 [189]. This effect was additive to that of SKF81297, a selective D1 agonist, and could be counteracted by quinpirole, a selective D2 agonist [190]. This result identified adenosine, via A2A receptors, as a key regulator of the phosphorylation state of DARPP-32 in striatopallidal neurones. Also in vivo the A2A antagonist SCH 58261 significantly counteracted the increase in DARPP-32 phosphorylation that was observed following treatment with selective D2 receptor antagonists [191], and the ability of D2 antagonists to increase DARPP32 phosphorylation was dramatically reduced in A2A receptor KO mice. As expected from the biochemical data, it was found that the ability of CGS 21680 to induce hypolocomotion was attenuated in DARPP-32 KO mice [192], and the ability of caffeine and SCH 58261 to induce hyperlocomotion was attenuated in DARPP-32 KO mice. A2A Receptor Antagonists and Parkinson’s Disease In parallel with the development of an increasingly clear understanding of the biochemical and molecular underpinning of the adenosine-dopamine interactions, there has been extensive work on the effectiveness of adenosine A2A antagonists in various experimental models of Parkinson’s disease. It will not be possible to present all these results. However, a study showed that A2A receptor antagonism could reduce not only symptoms of Parkinson’s disease, but also the loss of dopamine neurones induced by 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) [193]. Furthermore, it was shown that in fact persistent L-3,4dihydroxyphenylalanine (L-DOPA) effects require A2A receptors [194]. Thus, over the years the concept that A2A and D2 receptors interact in such a way, that A2A receptor antagonists could prove to be useful in Parkinson’s disease has developed. There are, however, concerns. One potential concern is related to tolerance. It is very well known that some actions of caffeine develop rapid tolerance [135,195]. However, caffeine effects in Parkinson’s disease models do not display tolerance [196], and there is also no tolerance to selective A2A antagonists in models that show tolerance to caffeine [197]. Another, and perhaps more serious, concern is related to the fact that A2A receptors regulate activities other than in


striatopallidal neurones. It has long been known that adenosine regulates platelet activation [198,199] and now it is known that A2A receptors are responsible for this mechanism [200,201]. Similarly A2A receptors are critically important in regulating neutrophil leucocyte activity [202] and activity of macrophages [203]. Even more importantly, A2A receptors do regulate inflammatory reactions in general [204,205]. Therefore, long-term blockade of adenosine A2A receptors might cause undesirable peripheral morbidity. Nevertheless, the development of A2A receptor antagonists for Parkinson’s disease is progressing in several companies and clinical results are somewhat encouraging [206]. ADENOSINE RECEPTORS IN NEUROGLIA Astrocytes Astroglial cells possess all the known subtypes of adenosine receptors and they control metabolism of carbohydrates, astrogliosis and the release of neuroactive substances (reviewed in [207]). Not all effects are receptor mediated. For example, adenosine- (and inosine)-mediated reduction of cell death in glucose deprived astrocyte cultures [208], appears to be due to intracellular formation of ribose-1-phosphate, which is able to fuel the intracellular ATP production. It is known that changes in astrocytes are among the earliest events following ischemia. Swelling in the perivascular part of astrocytes occurs early in ischemia. This swelling is enhanced by adenosine [209,210]. It is yet unclear which receptors are involved and also if this effect of adenosine is beneficial or detrimental. Swelling and other local processes after ischemia may be very important as they could compromise the blood-brain barrier, and if this fails there could be vascular oedema. Several mechanisms probably contribute to astrocytic swelling and swelling in turn affects astroglial function (see [211]). Reactive astrogliosis, the significance of which is unclear, has been reported to be activated by adenosine acting at an A2 receptor [212]. Besides A2 receptors, A3 receptors may mediate astrogliosis [213], whereas A1 receptors inhibit reactive astroglyosis [214]. Adenosine in the low physiological concentration range (10 nM) inhibits glutamate uptake via GLT-1 transporters through A2A adenosine receptors in vitro [215]. It also stimulates glutamate release from astrocytes via A2A receptors/ PKA pathway, independently from GLT-1. Thus, adenosine actions on glial cells rather than neurones might explain A2A receptor-mediated potentiation of hippocampal glutamatergic transmission [215-217]. Astrocytes also play an important role by providing glucose for neurones by breaking down glycogen [218,219]. Astrocytes can influence neuronal metabolism in numerous other ways. All of these metabolic pathways are potentially influenced by adenosine, particularly via A2 receptors (both A2A and A2B). A recent study [91] has demonstrated that stimulation of primary mouse astrocytes with the somewhat specific A 3 receptor agonist 2-chloro-N6-(3-iodobenzyl)-N-methyl-5´carbamoyladenosine, induces the release of the chemokine CCL2 through a Gi protein-independent pathway. Thus, adenosine acting on the A3 receptor appears to modulate the level of a chemokine that can exert both neuroprotective and detrimental effects. Adenosine is able to enhance the produc-


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tion of other important neuroprotective substances, such as nerve growth factor (NGF), transforming growth factor-1 and S100 , in cultured astrocytes via activation of A1 receptors [207,220] The increase in interleukin-6 (IL6) synthesis and secretion induced by adenosine is inhibited by the nonselective adenosine receptor antagonist, 8-(psulfophenyl)theophylline, but not by specific A1 or A2A antagonists [220]. Furthermore, signalling via A2B receptors is influenced by interleukins in parallel with the generation of NGF [221]. Oligodendrocytes Perinatal hypoxia is prevalent and can lead to permanent damage, often related to white matter loss. In rodents perinatal hypoxia can lead to periventricular leukomalacia [222]. This can be mimicked by increases in adenosine due to genetic targeting of adenosine deaminase [223]. Furthermore, the resulting increase in cerebral ventricles is abolished in mice lacking A1 receptors and reduced in mice with only one copy of the A1 receptor gene. This indicates that in this particular situation adenosine is clearly having detrimental actions by influencing a glial cell or its precursor. Microglia Apparently, adenosine receptor expression profiles, as described in the literature, depend on the nature of the microglia preparation. Functional and pharmacological data have shown that adenosine receptors are expressed on microglia cells. However, results vary concerning the expression of the different adenosine receptor subtypes (for example functional and molecular data) strongly indicate the presence of A1 receptors [91,224], but using PCR adenosine A2A, A2B, and A3, but no A1 receptors were expressed in primary mouse microglia and the cell lines BV-2 and N13. In our hands, it was also absent from mouse primary microglia cells [225]. The role of adenosine A2A receptors has been described in detail with respect to the cAMP-mediated regulation of NGF, cyclooxygenase and K+ channel expression as well as microglia proliferation. The adenosine A2B receptor, on the other hand, has only been detected by RT-PCR and no information on the presence of functional A2B receptors and their role for microglia cells is available. Adenosine A3 receptors are present and functional in mouse immortalized microglia cell lines and primary isolated microglia cells [91, 225]. P2X PURINOCEPTORS IN NEURONES Expression Purinoceptors of both P2X and P2Y types are widely expressed in the brain. Autoradiographic studies demonstrated that binding sites for P2X specific radioligand, ([3H],-methylene ATP (,-meATP)) are present in all brain areas with the highest density in cerebellar cortex [226]. Expression of all 7 subunits of P2X receptors in nerve cells was reported at both mRNA and protein levels (see [227,228] and Table 1), although the precise allocation of subunits to different types of neurones remains to be characterised. Incidentally, every neurone type studied so far has at least some expression of ionotropic subunits. Generally, the P2X2, P2X 4


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Table 1. Brain region

mRNA

Protein

Reference

Cerebral cortex

P2X1, P2X2, P2X4 , P2X6

P2X2, P2X4

[63,693-697]

Olfactory bulb

P2X2, P2X4, P2X6

P2X2, P2X4

[63,693,695,697,698]

Hippocampus, CA1 - CA3 areas

P2X1, P2X2, P2X4 , P2X6

P2X2, P2X4

[63,694-699]

Medial habenula

P2X2, P2X4, P2X6

P2X2

[63,693-695]

Supraoptic nucleus

P2X2, P2X3, P2X4 , P2X6

P2X2, P2X4

[63,693-695,699-701]

Tuberomammillary nucleus

P2X2, P2X4, P2X6

P2X2

[63,693,700]

Substantia nigra zona compacta

P2X2, P2X4, P2X6

P2X2

[63,693,702]

Ventral tegmental area

P2X2, P2X4, P2X6

P2X2

[63,693,702]

Mesencephalic trigeminal nucleus

P2X2, P2X4, P2X5 , P2X6

P2X2, P2X4

[63,695,699]

Locus coeruleus

P2X2, P2X4, P2X6

P2X2

[63,693,695,702]

Motor trigeminal nucleus

P2X2, P2X4, P2X6

P2X2

[63,693,696]

Vestibular nuclei

P2X2

P2X2

[63]

Dorsal motor nucleus of vagus

P2X2, P2X4, P2X6

P2X2

[63,693]

Hypoglossal nucleus

P2X2, P2X4, P2X6

P2X2

[63,693]

Nucleus tractus solitarus

P2X2, P2X4, P2X6

P2X1, P2X2, P2X3 , P2X4, P2X5, P2X6

[63,693,702-706]

P2X2, P2X4, P2X6

[705,706]

Area postrema Rostral ventrolateral medulla

P2X2

P2X1, P2X2, P2X3 , P2X6

[63,706-709]

Cerebellar Purkinje cells

P2X1, P2X2, P2X3 , P2X4, P2X6

P2X1, P2X2, P2X3 , P2X4

[64,315,693,696,697,699,710,711]

Cerebellar granular layer

P2X1, P2X2, P2X4 , P2X6

P2X1, P2X2, P2X4

[64,315,693,696,697,699]

Cuneate nucleus

P2X1, P2X2, P2X3 , P2X4, P2X5, P2X6

[706]

Periaqueductal gray matter

P2X1, P2X2, P2X3 , P2X4, P2X5, P2X6

[712]

P2X2

[63,697,713,714]

P2X4

[699]

Facial nucleus

P2X2, P2X4, P2X6

Thalamus Dorsal striatum

P2X1

and P2X6 subunits are the most abundant in nerve cells and usually several subunits of P2X receptors co-localise in the same neurone. P2X Receptor-Mediated Currents in Neurones ATP-induced currents, indicative of operative P2X receptors, have been recorded from neurones in brain slices as well as in acutely dissociated or cultured neurones (Table 2). Generally, the single-cell responses demonstrated heterogeneous kinetics and pharmacological properties that most likely resulted from expression of several P2X subunits (Fig. (1)). It seems that central neurones express mixtures of hetero- and/or homomeric P2X receptors and relative expression may vary from neurone to neurone.

[694]

P2X Receptors in the Brain are Ca2+ Permeable The P2X receptors expressed in the brain are, as a rule, highly Ca2+ permeable [49,229,230]. The ratio of Ca2+ to monovalent cation-permeability for brain P2X receptors PCa/PCs : 10 – 12 [49,56,231], is similar to that for NMDA receptors and neuronal nicotinic ACh receptors (PCa/PCs = 4 10 [49]). This corresponds to fractional Ca2+ currents in the range of ~ 10% - 15% and indeed similar values were reported for several P2X expressing cellular preparations. For example, P2X receptor fractional calcium currents were determined as 8% for recombinant human P2X4 receptors [232]. In HEK cells expressing various homo- and heteromeric P2X receptors, the fractional currents were in the range of 4 – 14 % [229]. In superior cervical ganglia neurones, which express homomeric P2X2 receptors, the frac-



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Table 2. Brain region

Properties of ATP-induced currents

Reference

Hippocampus

Exogenous ATP induced inward currents and [Ca2+]i transients in hippocampal neurones. The P2X receptors mediated ~ 15 - 20% of the evoked EPSCs as judged by pharmacological sensitivity.

[53,253,715]

Supraoptic nucleus

ATP triggered inward currents; ATP and P2X agonists ATPS and 2-MeSATP and BzATP induced [Ca2+]i increase.

[701]

Trigeminal mesencephalic th nucleus of the V nerve

ATP, ATPS and ,-meATP triggered inward currents, sensitive to suramin. In outside-out patches the single ATP-gated channels with unitary conductance 22 pS were detected

[716]

Locus coeruleus

ATP and its analogues 2-MeSATP, ADP, ,-meATP triggered inward Na+ currents. The P2X currents were inhibited by PPADS

Medial habenula

Stimulation of neuronal terminals triggered ATP-mediated EPSCs; exogenous ATP induced cationic currents; both P2X-mediated EPSCs and ATP-induced currents were inhibited by suramin

[47,50,231,243]

Hypoglossal nucleus

Exogenous ATP applied to acute slices and in vivo excited hypoglossal nerve and triggered inward currents in motoneurones. ATP effects were blocked by suramin.

[718]

Acute slices

[52,717]

Dissociated/cultured cells Cortex

ATP triggered inward currents with variable kinetics and sensitivity to P2X inhibitors (suramin, PPADS, NF023) and positive modulator ivermectin in acutely isolated neurones

[55,56,255]

Hippocampus, CA1

Exogenous ATP (20 M) and ,-meATP triggered inward currents in acutely isolated pyramidal neurones

[253]

Supraoptic nucleus

ATP and BzATP caused inward currents, although no evidence for P2X7 responses was obtained. Both desensitizing (presumably P2X3) and nondesensitizing currents were observed in different cells.

[701]

Tuberomammillary nucleus

In nystatin-patch clamp experiments on acutely isolated neurones ATP triggered sustained cationic current.

[719]

Dorsal motor nucleus of vagus

In acutely dissociated preganglionic neurones triggered inward current which was inhibited by Reactive Blue 2 and suramin

[720]

Mesencephalic nucleus of Vth nerve

In cultured neurones ATP and ,-meATP triggered desensitising (presumably P2X3) current inhibited by suramin.

[721]

Nucleus of the solitary tract

ATP and 2-MeSATP triggered slowly desensitizing inward current in acutely dissociated neurones.

[722]

tional Ca2+ current was ~ 6.5 % [233]. Therefore the fractional Ca2+ currents through P2X receptors are similar to NMDA receptors (~ 10% [234]) and are larger than that for ACh receptors (3 - 7% [235-237]).

are naturally complex and involve both P2Y-mediated Ca2+ release from the intracellular stores and P2X-mediated Ca2+ influx [240,241].

Functionally, however, P2X receptors differ from NMDA receptors because of the absence of Mg2+ block; P2X receptors are therefore available for activation at all levels of membrane potential, whereas NMDA receptors require membrane depolarisation to ~ -40 mV [238,239]. Therefore, P2X receptors can create substantial Ca2+ fluxes at the resting membrane potential, when in fact they may be the major mechanism for Ca2+ entry. Indeed, exogenous ATP induces Ca2+ signals in many types of central neurones; these signals

ATP-Mediated Fast Synaptic Transmission ATP acts as an excitatory neurotransmitter in synapses throughout the brain (see [3-5] for review). The ATP release from neuronal terminals is accomplished by exocytosis [22,23]. ATP is accumulated in synaptic vesicles by a Cl-dependent vesicular nucleotide transporter (VNUT). This transporter, which was recently cloned, belongs to the SLC17 anion transporter family [242]. The VNUT is abundantly expressed in the brain, although its specific presence


Burnstock et al.

Fig. (1). "Mosaic" functional properties of P2X receptor-mediated currents in acutely dissociated pyramidal neocortical layer V neurones. A - D: examples of P2X currents recorded from 4 different neurones. In A, B the traces represent (from left to right) control response to ATP (20 μM); inhibitory action of action of PPADS (30 μM); response to ATP after washout of drug. In C and D examples of currents evoked by various agonists of P2X receptors are demonstrated. The traces represent (from left to right) response to ATP (20 μM); response to ,-methylene ATP (25 μM); response to ,-methylene ATP (20 μM). Recordings were made with 5min time interval between applications at a holding potential of -80 mV. Reproduced from [56] with permission.

in synaptic vesicles has not been demonstrated yet. The concentrations of ATP in synaptic vesicles can vary from several to ~ 50 - 100 mM [23], and in different parts of the brain ATP can be co-stored and co-released from vesicles with other neurotransmitters (for example with glutamate, GABA or NA). Alternatively, ATP can be stored on its own in a special pool of vesicles, which can be the sole inhabitants of terminals (as in medial habenula [243]) or may share the presynaptic terminal with glutamate-containing vesicles [22]. ATP-mediated fast synaptic transmission was initially suggested by Wieraszko and Seyfried [244] and experimentally demonstrated by Edwards et al. [50] in slices from medial habenula and by Evans et al. [245] in cultured celiac ganglion cells. In the following decade P2X-mediated postsynaptic currents were recorded in neurones from many

brain regions, including hippocampus [53, 54], locus coeruleus [52] and somatosensory cortex [55,56]. In the majority of CNS synapses ATP is released together with other transmitters; currently, the only region where pure ATP-mediated transmission exists in terminals is the medial habenula [243]. The ATP-mediated component of synaptic transmission (Fig. (2), Fig. (3)) in central synapses represents, as a rule, a minor component of fast excitatory postsynaptic current (EPSC); the amplitude of P2X-mediated EPSC rarely exceeds ~ 5 15% of the EPSC mediated by glutamate receptors [23, 49]. The functional role of P2X-mediated excitatory transmission remains controversial; most likely it is involved in fine tuning of the synaptic strength and regulation of synaptic plasticity.



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Fig. (2). Separation of the P2X receptor-mediated component of excitatory postsynaptic currents (EPSC) in cortical pyramidal neurones. A. Top, changes in the amplitude of EPSC following bath application of glutamatergic antagonists NBQX and D-AP-5, cholinergic antagonist HEX and P2X receptor antagonist, NF023, as indicated on the graph. Each point represents mean ± SD for six sequential trials, holding potential -80 mV, stimulation frequency 0.1 Hz. Bottom, the examples of residual EPSC (average of six traces) recorded at moments (1-5) indicated on upper graph. B. Changes in the amplitude of non-glutamatergic EPSC following bath application of the serotonergic antagonist, Y-25130, and the P2X receptor antagonist NF279. Recordings were made at a holding potential of -80 mV in the presence of NBQX, 10 μM, D-AP5, 30 μM and bicuculline, 20 μM, stimulation frequency 0.1 Hz. Each point represents mean ± SD for six sequential trials. Reproduced with permission from [55].

P2X Receptors and Synaptic Plasticity The long-lasting regulation of synaptic strength is represented by the LTP and long-term depression (LTD), which are regarded as electrophysiological correlate of learning and memory [246-248]. The mechanisms underlying these forms of synaptic plasticity can vary in different brain regions; conceptually these may be either presynaptic (modulation of

neurotransmitter release) or postsynaptic (modulation of postsynaptic receptor availability and/or properties). Often the signal initiating LTP/LTD is associated with cytoplasmic Ca2+ signals, which, in turn, activate various signalling cascades that affect synaptic strength. There is a substantial amount of evidence indicating a role for neuronal P2X receptors in regulation of synaptic


plasticity [49]. In certain conditions over-activation of P2X receptors can trigger either LTP or LTD [249-251], although this action most likely occurs in a pathological context associated with massive release of ATP during, for example, brain ischemia [252]. In physiological conditions, activation of P2X receptors was reported to modulate long-term plasticity in several brain areas.

Burnstock et al.

In the CA1 area of hippocampus, inhibition of P2X receptors facilitated the induction of ATP, probably because of removal of P2X receptor-dependent Ca2+ inactivation of NMDA receptors [253]. At the same time purinergic signalling is involved in regulation of LTD in CA1, CA2 and dentate gyrus; genetic deletion of the P2X3 subunit led to LTD inhibition. Incidentally, impaired LTD did not prevent genetically modified mice performing well in spatial learning tests [254]. On the contrary, activation of P2X4 receptors seems to enhance LTP in the CA1 hippocampal area, because positive modulation of P2X4 receptors by ivermectin [255] facilitated LTP induction, whereas genetic deletion of the P2X4 subunit reduced LTP [256]. The reason for these controversial findings remains obscure, although it may well be that P2X receptors can produce opposite effects on synaptic plasticity depending on the physiological context and degree of activation. Neuronal Expression of P2X7 Receptors The presence of P2X7 receptors in nerve cells and their possible functional roles represents a controversial topic (discussed in great detail in, for example, the excellent review by Andersen and Nedergaard [257]). P2X7 receptors differ from other members of the P2X family in their low ATP sensitivity, almost complete absence of desensitization and ability to produce large transmembrane pores upon intense stimulation [228,258]. Initial attempts to localise brain P2X7 receptors have demonstrated their exclusive expression in the ependymal layer of the third ventricle [259]. Subsequently, both P2X7 receptor mRNA and immunoreactivity was detected in various brain areas, including hippocampus, cortex and brain stem, medulla oblongata, cerebellum, thalamus and amygdala (see [260] for review). At the same time the specificity of many antibodies used for P2X7 receptor immunostaining remains inadequate, thus making many of these observations questionable [257, 261].

Fig. (3). Voltage dependence of the P2X receptor-mediated EPSC component in cortical pyramidal neurones. A. Representative EPSCs recorded in the presence of NBQX, 20 μM, D-AP5, 60 μM and bicuculline, 20 μM at a membrane potential range from -100 to +40 mV. Each trace represents the average of six consecutive sweeps. The intracellular concentration of Cl- was 120 mM. B. Voltage-current relationship for the purinergic EPSC measured at different intracellular concentrations of chloride ions. Amplitudes of currents were normalized to the maximal value measured at -80 mV. Each point is the mean ± SD for 7 cells. Lines represent the cubic polynomial fit. All the measurements were in the presence of NBQX, 20 μM, D-AP5, 60 μM and bicuculline, 20 μM. Note the lack of changes in the voltage-dependence of EPSC indicating negligible contribution of chloride conductance. Reproduced with permission from [55].

Similarly, electrophysiological recordings in situ failed to detect P2X7 receptor-mediated postsynaptic responses or P2X7 currents in response to exogenous ATP. The presumed P2X7 receptor-mediated [Ca2+]i responses were recorded in synaptosomes and neuronal cultures [262]; these data, however, could be regarded as an in vitro artefact. Several groups reported the presynaptic role for P2X7 receptors; these findings relied mostly on the effects of 2’-&3’-O-(4-benzoylbenzoyl)-ATP (BzATP), which rapidly degrades to Bzadenosine, which may then act via A1 receptors [263-265]. The physiological importance of P2X7 receptors in the brain, however, remains obscure. P2Y RECEPTORS IN NEURONES At least seven types of P2Y receptors (P2Y1,2,4,6,11,12,13) were detected in the brain at both the mRNA and protein levels (see [266] for comprehensive review). The largest mRNA expression was found for P2Y1 and P2Y11 receptors, and subsequent immunohistochemistry found high levels of neuronal expression for P2Y1. This receptor was identified in nerve cells from the cerebral cortex, cerebellar cortex (specifically in Purkinje neurones), hippocampus, medial habenula, corpus callosum, caudate nucleus, putamen, globus


pallidus, subthalamic nucleus, red nucleus and midbrain [66, 67]. The main functions of neuronal P2Y receptors are represented by initiation of intracellular Ca2+ signals and by regulation of neuronal ion channels. The Ca2+ mobilising activity of P2Y receptors is well characterised in various tissues and it is realised through G protein/phospholipase C (PLC)/inositol trisphosphate (InsP3) signalling cascade with subsequent Ca2+ release from the endoplasmic reticulum (ER) stores [267, 268]. The P2Y-mediated Ca2+ signalling was detected in neurones in vitro and in situ. For example, in cultured hippocampal and thalamic neurones, ATP triggered ER Ca2+ release in about 30% of cells. This Ca2+ mobilising effect was substantially potentiated by pre-treatment with inhibitors of protein kinase C, H-7 or staurosporine [269]. UTP stimulated PLC/InsP3 driven Ca2+ release in cultured newborn neocortical neurones; this release was inhibited by the InsP3 receptor blocker heparin [270]. P2Y-mediated Ca2+ signals were also recorded and characterised in detail in neocortical neurones [241] and in Purkinje neurones [240] in acute slices as well as in the hair cells in isolated cochlea preparations [271]. There is a wealth of data documenting P2Y-mediated regulation of neuronal voltage-gated Ca2+ channels. Stimulation of P2Y receptors with ATP and ADP induced pertussis toxin-sensitive inhibition of N- and P/Q types of Ca2+ channels in chromaffin cells [272-274], in frog sympathetic neurones [275] and in neuroblastoma cells [276]. The multitude of P2Y receptors (P2Y1,2,4,6,12) artificially expressed in rat superior cervical ganglion neurones induced inhibition of voltage-gated Ca2+ channels via G proteins [277]. In a similar way P2Y receptors were reported to inhibit M-type K + currents in sympathetic neurones [278, 279]. Furthermore, various P2Y receptors activate outwardly rectifying K+ currents in neurones isolated from striatum [280], hippocampus [281] and cerebellum [282]. Physiological stimulation of P2Y receptors affects synaptic transmission in various brain regions mainly by regulating the release of neurotransmitters. In hippocampus, activation of presynaptic P2Y receptors inhibits the release of glutamate in excitatory synapses [283]. In the medial habenula presynaptic P2Y2 receptors inhibit whereas P2Y4 receptors potentiate synaptic glutamate release [284]. There are also data demonstrating P2Y-mediated inhibition of the release of serotonin and NA in cortical structures [285, 286]. P2X PURINOCEPTORS IN NEUROGLIA Neuroglia, represented by several major classes (astrocytes, oligodendrocytes, NG2 glia and microglia, see [89,287-289]) represents the main cellular homeostatic element of the brain. The functions of neuroglia are many; these cells define the microarchitecture of the nervous system, control brain microenvironment and brain defence, regulate neurogenesis and provide for neural cells migration, and, in all likelihood, have a role in information processing in neural circuits [290,291]. Furthermore, neuroglia are intimately involved in neuropathology, determining to a very great extent the progress and outcome of various diseases of the nervous system [105, 292-295].


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ATP plays an important role in neuronal-glial and glialglial communications, since every type of glial cell possesses purinoceptors (see [6,104,296-305] for reviews). Furthermore, ATP acts as a principal gliotransmitter, which is released from neuroglial cells either through exocytosis or through diffusion via high-permeability plasmalemmal channels, such as volume-regulated chloride channels and hemichannels of dilated P2X7 receptors [24,27,94,306-308]. Astrocytes Functional expression of P2X receptors in astrocytes is poorly characterised [6]. Expression of P2X subunit specific mRNA was detected in astrocytes both in vitro and in situ. mRNA for P2X1-5 and P2X7 subunits was found in primary cultured astrocytes [309,310]. In dissociated rat Müller cells P2X3, P2X4, P2X5 but not P2X7 receptor mRNAs were identified [311]; conversely P2X7 receptor mRNA was found in human Müller glia [312]. In dissociated cortical astrocytes, the P2X1 and P2X5 specific mRNA was predominantly expressed [313]. At the protein level P2X2,3,4 immunoreactivity was found in GFAP-positive astrocytes from nucleus accumbens [314]. P2X1 and P2X2 receptors were visualised in astroglial cells in cerebellum [64,315] and P2X4 receptors in astrocytes from brain stem. Immunostaining of hippocampal astrocytes detected expression of P2X1-4, P2X6 and P2X 7 subunits [316]. Electrophysiological experiments revealed ATP-induced depolarisation and membrane currents with accompanying [Ca2+]i rises in cultured astrocytes, although the subunit composition of the underlying receptors was not investigated [317,318]. P2X-mediated currents were not detected in hippocampal astrocytes or in cerebellar Bergmann glial cells [319,320]. In cortical astrocytes, ATP triggered inward currents, which resulted from the activation of heteromeric P2X1/5 receptors (Fig. (4)); the latter display a very high (EC50 ~ 50 nM) sensitivity to ATP and very little desensitisation in the presence of the agonist [313]. In astrocytes from the acutely isolated optic nerve, ATP triggered large increases in [Ca2+]i, which were partially blocked by the P2X antagonist NF023 and could be mimicked by the P2X agonist ,-meATP [321]. Functional expression of P2X7 receptors in astroglia is also controversial. P2X7 receptor expression in cultured astrocytes has been demonstrated by many groups at both the mRNA and protein levels [309,310,322-326]. Immunoreactivity for P2X7 receptors was also found in freshly isolated astrocytes and in some astrocytes in brain slices [316,327]. Conversely, recently performed, in depth analysis of the cellular distribution of P2X7 mRNA in the rat brain using isotopic in situ hybridization, found its presence in microglia, oligodendrocytes and neurones in many brain areas, yet it failed to detect any presence of P2X7 mRNA in astroglia [328]. On a functional level, activation of P2X7 receptors induced Ca2+ signals in cultured astrocytes [310,329,330] and in astrocytes in the acutely isolated optic nerve [321], whereas voltage-clamp experiments revealed typical P2X7 mediated currents in cultured cortical astrocytes [322] and in Müller cells freshly isolated from human retina [312]. Nonetheless, P2X7 responses are rarely observed in grey matter


Burnstock et al.

Fig. (4). P2X1/5 receptor-mediated currents in cortical astrocytes. A. The family of ATP currents evoked by repetitive applications of the agonist. The currents show no apparent desensitisation. Current traces have complex kinetics comprising the peak, the steady-state component and the “rebound” inward current recorded upon ATP washout as indicated on the graph. B. Concentration-dependence of ATP-induced currents in cortical astrocytes. Membrane currents recorded from a single cell in response to different ATP concentrations are shown on the left. The right panel shows the concentration response curves constructed from 9 similar experiments; current amplitudes were measured at the initial peak and at the end of the current, as indicated on the graph. Reproduced with permission from [313].

astrocytes in situ. Treatment of hippocampal slices with BzATP induced sustained currents in neurones, which was explained in terms of P2X7-mediated release of glutamate from astrocytes. The neuronal responses were blocked by Brilliant blue G (BBG) and oxidised ATP (oxATP); voltageclamp experiments revealed sustained currents and depolarisation of striatum astroglia [331]. At the same time, authors concluded that P2X7 receptor activation most likely occurs only in pathological conditions, where astroglial glutamate release may further exacerbate the grey matter damage [331]. Therefore it is possible to suggest that astroglial P2X7 receptors are mostly involved in pathological reactions; there are indications that their expression is up-regulated following various types of brain insults [6,332]. Indeed, activation of P2X7 receptors can be pathologically relevant as numerous experiments on cultured astroglia (which are by definition reactive) had demonstrated that opening of P2X7 channels triggers release of glio-transmitters [100,308,322,329], increases astroglial production of endocannabinoids [333],

regulates release of tumour necrosis factor- (TNF-) [334], stimulates nitric oxide (NO) production [325,335] and regulates nuclear factor-B signalling [324]. Oligodendrocytes Expression of P2X1,2,3,4,7 proteins was detected in cultured oligodendroglial progenitors [336,337]. P2X-mediated currents, however, were not detected in mature oligodendrocytes in situ [338], although in astroglial cells in the optic nerve preparation, ATP-induced [Ca2+]i elevations were partially blocked by P2X antagonists [339]. There are some indications, however, that P2X7 receptors may be operational in oligodendrocytes in white matter tracts. The immunoreactivity for P2X7 receptors was detected in oligodendrocytes from the optic nerve and the spinal cord [340,341]. Functional P2X7 receptors were found in the cells of oligodendroglial lineage in vitro. Application of BzATP triggered oxATP-sensitive Ca2+ signals in cultured


oligodendroglial precursors [336]. In oligodendrocytes cultured from optic nerve, high millimolar concentrations of ATP and BzATP induced sustained inward currents and Ca2+ signals, which were potentiated in divalent-cation-free extracellular solutions and were inhibited by oxATP [341,342]. At the same time P2X7 receptors in oligodendrocytes may specifically operate in pathological conditions, and indeed in experimental autoimmune encephalomyelitis (an animal model for multiple sclerosis) treatment with oxATP and BBG ameliorated demyelination and restored nerve conduction velocity [340,342]; increased levels of P2X7 receptor expression was also found in white matter of multiple sclerosis patients [342]. Microglia Microglial cells are the innate brain defence system which is intimately involved in virtually all types of neuropathology. Brain damage is always associated with massive release of adenosine and ATP, and therefore it is not surprising that both agents act as powerful stimulators of microglia that initiate numerous and complex programmes of microglial activation. The activation of microglia is manifested by phenotype remodelling, chemotaxis and release of cytokines and pro-inflammatory factors [105,343-345]. Microglial cells express a wide spectrum of purinoceptors, expression of which depends on the activation status [297,346,347]. The majority of resting microglia constitutively express P2X4 and P2X7 receptors, expression of which undergoes complex changes upon microglial activation [348,349]. P2X4 receptors are specifically important in neuropathic pain (discussed in detail in the Section below). P2X7 receptors are operative in microglia in vitro and in situ, which was supported by both electrophysiology [350] and Ca2+ imaging [351-353]. Expression of microglial P2X7 receptors is markedly increased in various types of brain pathology, including traumatic damage, ischemic insults and various neurodegenerative processes, such as, for example, in Alzheimer's disease and multiple sclerosis [259,354-357]. P2Y PURINOCEPTORS IN NEUROGLIA Astrocytes Metabotropic P2Y receptors are abundantly expressed in astrocytes throughout the brain. Expression of the P2Y subtypes (P2Y1,2,4,6,12,13 and uridine diphosphate (UDP)-glucose P2Y14) was found at both the mRNA and protein levels in primary cultured, as well as by in situ, in astrocytes from different brain regions, although the P2Y1,2,4,6 receptors seem to be dominant (see [6, 296, 309, 310, 332, 358-361]). Functionally, astroglial P2Y receptors are coupled to Ca2+ signalling through the PLC/InsP3 pathway. Exogenous ATP and other P2Y agonists trigger P2Y-driven Ca2+ release from the ER, which is often followed by store-operated calcium entry, in astrocytes in culture and in situ, in brain slices [320,339,362-373]. As a rule, P2Y1 and P2Y2 receptors dominate the nucleotide-induced Ca2+ signalling in astroglia; these receptors are particularly important for the generation and maintenance of propagating glial Ca2+ waves [24, 374, 375]. P2Y1 receptors are also important for astroglial [Ca2+]i oscillations [376, 377].


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P2Y metabotropic receptors are also specifically involved in the release of gliotransmitters. ATP stimulation of cultured and optic nerve astrocytes stimulates ATP release via several mechanisms (Ca2+-regulated exocytosis and diffusion through hemichannels and/or volume-sensitive Clchannels [97,306,321,378,379]); activation of P2Y receptors is also instrumental in stimulating astroglial release of glutamate, aspartate and D-serine [380,381]. The predominant ATP-induced gliotransmitter pathway is, however, exocytotic, for which ample physiological and pharmacological evidence is available [24,87,98,382-385]. Finally, P2Y receptors are involved in regulation of astroglial differentiation and morphological remodelling of astrocytic processes, and astroglial development and other trophic actions [3,296,386,387]. Oligodendrocytes It seems that P2Y1 receptors represent the main type of oligodendroglial P2 receptor [67,388], although some expression of P2Y2,4 was detected in cultured oligodendroglial precursors [388]. Stimulation of P2Y receptors triggers intracellular Ca2+ release in cultured oligodendrocytes, but not in O4-negative precursor cells [338]. Similarly, ATP evokes Ca2+ signals in oligodendrocytes in situ in corpus callosum slices and in the optic nerve [338,389,390]. This Ca2+ signalling originates through P2Y/PLC/InsP3-induced Ca2+ release from the ER stores [338]. Microglia The predominant expression of P2Y2, P2Y6, P2Y12 and P2Y13 was found in microglia in vitro and in situ [391,392]; activation of these receptors triggers Ca2+ signals originating from ER Ca2+ release and store-operated Ca2+ entry [392394]. Activation of P2Y receptors in ramified microglia in brain slices also triggers outward K+ currents [395]. P2Y receptors also regulate secretion of cytokines from activated microglia [396-398]. P2Y6 receptors are specifically linked to phagocytic activity of activated microglial cells [399], whereas P2Y12 receptors are responsible for early initiation of microglial activation [301,400]. Finally some microglial cells in the lesioned brain area were reported to express a novel P2Y-like receptor, GRP17, sensitive to UDP, UDPglucose, UDP-galactose and to cysteinyl-leukotrienes LTD4 and LTC4 [401]. PURINOCEPTORS IN CEREBRAL VESSELS Adenosine dilates cerebral blood vessels [402-404] via P1 receptors [405-407]. ATP was shown early to be a more potent dilator of cerebral vessels than adenosine in the baboon and cat [408,409] and goat [410]. Surprisingly high concentrations of ATP were shown to be released from brain tissue to affect local blood flow [411]. Intra-carotid infusion of ATP increased cerebral blood flow in anaesthetised baboons by about 90%, while adenosine increased it by less than 10%; further application of ATP and adenosine produced pial arteriolar dilations [412]. Adenosine is taken up by bovine cortex capillaries and converted to ATP and is associated with the activation of the blood-brain barrier [413,414]. Adenosine causes dilation of rabbit hypothalamic blood vessel smooth muscle at low concentrations, but con-


striction at high concentrations [415]. A2 receptors were identified mediating relaxation of cat cerebral arteries [416] and of rabbit cerebral microvessels [417]. It has been claimed that human cerebral microvessels have A2, but not A1, receptors [418]. The same appears to be the case for porcine basilar arteries [419], goat cerebral vessels [420] and rat pial arterioles [421]. Both A2A and A2B receptors were later identified on vascular smooth muscle mediating vasodilation in rat cerebral cortex [422,423]. In rat pial arteries A2B receptors were also present on endothelial cells mediating vasodilation via NO [424,425]. A2A receptors mediate glutamateevoked arteriolar dilation in the rat cerebral cortex [426]. A1 and A3 receptor subtypes have been identified in rat pial and intracerebral arteries [427]. Adenosine receptors were described on capillary vessels in the rat brain [406]. Inosine potentiates adenosine-evoked vasodilation in pial arterioles. In an important early study of pial arteries from the rabbit, cat and man, it was shown that ATP, acting on P2 receptors on smooth muscle, elicited contraction, while adenosine acting via muscle P1 receptors caused relaxation, and further that ADP and ATP acting on P2 receptors on endothelial cells caused relaxations [428]. UTP and UDP induced longlasting contraction of isolated brain arteries in humans [429] and dogs [430]. In the rabbit basilar artery UTP, as well as ATP, caused contraction by two distinct receptors [431], in retrospect by P2X and P2Y2 receptors. ,-MeATP produced potent contraction of goat middle cerebral artery [420], suggesting mediation via P2X1 receptors. UTP also constricted the middle cerebral artery [432], consistent with mediation via a P2Y2 receptor. Constriction of rat cerebral (pial) microvasculature is mediated by muscle P2X1, P2Y2 and P2Y6 receptors, a finding supported by both functional and RT-PCR studies [433]. UTP-induced cerebrovascular constriction in the rat involves release of prostanoids [434]. Potent P2Y6 receptor-mediated contraction of human cerebral arteries has been reported [435]. P2Y6 receptors were also described as the most potent receptor mediating constriction of the rat basilar artery, with lesser contributions from P2X1 and P2Y2 receptors [436]. [Ca2+]i increase and membrane depolarisation caused by P2X receptor-mediated current in rat cerebral artery smooth muscle cells may regulate the subsequent P2Y receptor responses [437]. All InsP3 receptor isoforms are expressed in rat cerebral artery smooth muscle cells, with InsP3I dominant, which contributes to UTP-induced vasoconstriction [438]. UTP released Ca2+ waves in smooth muscle cells of rat basilar artery; this may underlie the tonic contractions produced by repetitive cycles of regenerative Ca2+ release from sarcoplasmic reticulum through InsP3-sensitive receptors [439]. In aging rat cerebral arteries, there is downregulation of P2X1 and upregulation of P2Y1 and P2Y2 receptor mRNA in smooth muscle cells and downregulation of P2Y1 and P2Y 2 receptor mRNA in endothelial cells [440]. Aging improves NO synthase (NOS)-dependent reactions of endothelial cells in rat cerebral arteries induced by ADP [441]. Mammalian homologs of the Drosophila transient receptor potential (TRP) channel have been identified in vascular smooth muscle cells. It has been shown that TRPC3 mediates UTPinduced depolarisation of smooth muscle cells in rat cerebral arteries [442].

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Sympathetic nerve stimulation constricted rabbit basilar arteries via two components, one NA, the other unknown at the time [443]. ATP produced contraction of canine basilar artery [444] and was later proposed to be released as a cotransmitter with NA from sympathetic nerve terminals [445]. Perivascular nerve stimulation of the guinea-pig and dog basilar arteries elicited excitatory junction potentials [446,447]. Receptors for ATP and adenosine were found at both pre- and post-junctional sites [448]. Prejunctional inhibitory effects of adenosine and AMP on neuromuscular transmission in cat cerebral arteries is mediated by A1 receptors [449]. Ca2+-ATPase was shown with electronmicroscopy to be localised on cerebral endothelium [450]. UTP and UDP relax human pial arteries via the endothelium [451], suggesting P2Y2 and/or P2Y4 receptors are involved. ADP dilation of rat cerebral arterioles is via NO release from endothelium [452]. Relaxation of rabbit small cerebral arteries to ADP was endothelium-dependent [453]. ATP produced relaxation of monkey temporal and cerebral arteries, which were endothelium-dependent in temporal arteries, but less so in cerebral arteries [454]. P2Y1 and P2Y 2 receptors were also identified on endothelial cells from bovine cerebral arteries [455,456]. ATP and UTP caused an increase in [Ca2+]i in the immortalized rat brain endothelial cell line, RBE4, perhaps via P2Y2 and/or P2Y4 receptors [457]. In bovine middle cerebral arterial strips without endothelium, UTP induced contraction, but with intact endothelium produced vasodilation via NO, but not prostacyclin [458]. ATP dilated rat middle cerebral arteries via endothelial P2Y1 and P2Y2 receptors, via release of NO [459]. Endothelium-derived hyperpolarising factor (EDHF), in addition to NO, mediates vasodilation of rat middle cerebral arteries via endothelial P2Y2 receptors by opening an atypical calcium-activated K+ channel [460]. In a comparative study of rat middle cerebral arteries, third order branches and penetrating arterioles, it was concluded that the role of NO in purinoceptor-evoked dilations diminishes along the cerebrovascular tree (artery to arterioles), whereas the role of EDHF becomes more prominent [461]. P2X2 receptors were localised with electron microscopy on vascular endothelial cells in rat brain [462]. Dilation of rat intracerebral arterioles by low concentrations of ATP was via P2Y1 receptors, while high concentrations activated P2Y2 receptors; NO was involved in P2Y1, but not P2Y2 receptor-mediated dilation [463]. ATP release from rat brain endothelial cells was claimed to be via connexin hemichannels [464]. It has been suggested that female rat pial arteriolar ADP-induced dilation as the result of additive contributions from P2Y1 receptors present on endothelium, but also on the glia limitans (GL) the underlying layer of astrocytic glial processes; the influence of the GL component is not altered by ovariectomy [465]. Long-term effects of UTP include chemotactic, mitogenic and angiogenic actions on vascular endothelial cells [466]. Cultured rat brain capillary endothelial cells show increase in [Ca2+]i in response to ATP [467]. In a later paper, two subtypes of receptors were identified in these cells: an ADP-specific receptor leading to release of intracellular Ca2+ (in retrospect a P2Y1 receptor) and a receptor that recognises ATP and UTP that is positively coupled to PLC (in retrospect a P2Y2 and/or P2Y4 receptor) [468]. P2Y1 receptors


were also identified on B10 cells, a cloned cell line of rat brain capillary endothelial cells [469]. Another paper claimed that in rat brain capillary endothelial cells, ATP activated P2Y2 receptors coupled to PLC, Ca2+ and mitogenactivated protein kinase (MAPK), and via P2Y1 receptors linked to Ca2+ mobilisation and a further unidentified receptor linked to increase in cAMP levels [470,471]. ADPases are present on rat brain capillary cells, which degrade ATP to ADP, and ADP to adenosine [472]. Diadenosine polyphosphates are antagonists to P2Y1 receptors on rat brain capillary endothelial cells [473]. P2Y12 receptors were claimed to be present on rat brain capillary endothelial cells as well as P2Y1 receptors [277,474]. TNF- inhibits purinergic calcium signalling in bloodbrain barrier endothelial cells by reducing gap junction coupling and inhibiting ATP release [475]. Adenosine, acting via A2B receptors on bovine brain capillary endothelial cells, has a functional role in the regulation of blood-brain barrier permeability [476]. Efflux transport of adenosine at the blood-brain barrier has been described [477,478]. In summary, vasoconstriction to ATP and UTP of cerebral arteries is mediated by P2X1 and P2Y2 receptors, respectively and vasodilation by A1 receptors on smooth muscle, and endothelium-dependent vasodilation by ADP via P2Y 1 and P2Y12 receptors, UTP via P2Y2 receptors and UDP via P2Y6 receptors. PURINOCEPTORS IN NEUROPATHOLOGY In the brain, P2 purinergic signalling is involved in the regulation of a variety of pathophysiological processes, including remodelling following trauma, stroke, ischaemia, or neurodegenerative disorders [119]. There is recent focus in particular on the potential therapeutic role of P2X7 receptor antagonists for the treatment of neurological and psychiatric disorders, including Alzheimer's disease, multiple sclerosis, inflammatory neuropathic pain and depressive illness (see [479]). Brain Injury and Neuroprotection Trauma Cellular damage can result in the release of large amounts of ATP into the extracellular environment, which might be important for triggering cellular responses to trauma [480]. Mechanical strain also causes ATP release from cortical astrocytes. Trauma-induced activation of purinergic signalling in astrocytes via P2Y4 receptors stimulates the synthesis and release of thrombospondin-1, an extracellular matrix molecule that induces synapse formation during development and might have a role in CNS repair and remodelling after injury [481]. In vivo, ATP released from astrocytes is essential for mediating the injury-induced defensive responses of microglia [482], establishing a potential barrier between the healthy and injured tissue [297]. Following brain trauma, activated P2Y12 and probably P2X4 receptors [400,483] stimulate the migration and chemotaxis of resting microglia to the site of damage, where they become transformed into the activated amoeboid form; an effect that is replicated by ATP [346]. In addition, P2Y6 receptors are upregulated to limit secondary damage by mediating the


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phagocytosis of debris [399]. Accumulation of P2X4 receptor-positive microglia and macrophages following experimental traumatic brain injury has been described [484]. Activated microglia also show significant changes in P2X7 receptor expression, which has an important role in controlling microglial proliferation and death [480,485]. Following neuronal injury, ATP can also act in combination with fibroblast, epidermal and platelet-derived growth factors, as well as NGF from both neurones and glial cells [7] to stimulate astrocyte proliferation, contributing to the process of reactive astrogliosis and to hypertrophic/hyperplastic responses [486]. P2 receptors stimulate the signal transducer and activator of transcription 3 (STAT3), suggesting that P2 receptor/STAT3 signalling could have an important role in astrocyte proliferation and reactive astrogliosis [487]. P2Y receptors mediate reactive astrogliosis, via induction of cyclooxygenase 2 (COX2), and P2Y receptor antagonists might counteract excessive COX2 activation in both acute and chronic neurological disease [488]. Cerebellar lesions result in upregulation of P2X1 and P2X2 receptors in precerebellar nuclei [489], and stab wound injury in the nucleus accumbens leads to increased expression of several subtypes of P2X and P2Y receptors [490]. A novel mechanism for inhibition of apoptosis in neuroprotection implicates parallel, interacting systems involving extracellular ATP acting through P2Y2 receptors and neurotrophin acting through TrkA receptors [491]. It has also been claimed that P2Y2 receptors activate neuroprotective mechanisms in astrocytes [492]. ATP released during trauma acts through P2 receptors to inhibit the release of the cytotoxic excitatory transmitter glutamate, but also stimulates the release of the inhibitory transmitter GABA from hippocampal nerves, thus serving a protective role [493]. The number of P2Y1 receptor-positive neurones and glial cells in the rat nucleus accumbens has been shown to be significantly increased after injury [494]. Oligodendrocytes can be killed by ATP, as well as by glutamate, released from damaged brain tissue in trauma injury or stroke, probably through P2X7 receptors [342]. Glycogen synthase kinase-3 (GSK-3) inhibition is vital for neurone survival and a study has shown that P2X7 receptor agonists promoted GSK-3 inhibition in cerebellar granule neurones and these effects and neuroprotection were abolished by P2X7 receptor antagonists [495]. The P2Y-like GPR17 has been identified as a sensor of brain damage and a novel target for brain repair [401]. Binding of NGF to ATP is a prerequisite for its neuroprotective effect [496]. Purinergic Signalling in Ischaemia The hypothesis of Berne, that adenosine is the physiological regulator of reactive hyperaemia [497], was supported for the cerebral circulation by some authors [498,499], but not by others, when the increase in blood flow that occurred in hypoxia was shown not to be clearly related to changes in adenosine concentration [500-502]. ATP, as well as adenosine, was measured in the perfusate of rat cerebral cortex during hypoxia [503]. Several reviews describing the roles of adenosine and adenine nucleotides as regulators of cerebral blood flow in hypertension, hypoxia/ischaemia and hypercapnia/acidosis have been published [504,505]. An


involvement of adenosine in cerebral blood flow regulation in hypercapnia has been reported [505,506]. A1 receptor agonists have been claimed to play a pivotal role in protection from hypoxic insults [507]. Hypoxia can induce upregulation of CD75 expression in brain microvessel endothelial cells [508]. Ischaemia can produce and exacerbate many serious insults to the CNS, including stroke and paralysis. Adenosine has an important protective role against ischaemic damage in the brain [509], although ATP, rather than adenosine, has been claimed to accelerate recovery from hypoxic/hypoglycaemic perturbation through a P2 receptor [510,511]. After transient forebrain ischaemia, ectonucleotidase is upregulated and there is an increased release of purines into cerebral cortical perfusates [512]. Upregulation of P2X2 and P2X4 receptors in cell cultures of hippocampus, cortex and striatum is associated with ischaemic cell death and was prevented by P2 receptor antagonists [513]. Following ischaemia, P2X7 receptors are upregulated on neurones and glial cells in rat cerebral cortex [354,355] and become hypersensitive in cerebrocortical cell cultures [514], although earlier studies showed that deletion of P2X7 receptors (KO mice) and/or treatment with the P2X7 receptor antagonist KN62 had little effect on ischaemic cell death [515]. Microglial P2X4 and P2X7 receptors might be involved in cortical damage produced by oxygen and/or glucose deprivation [349] and activation of P2X receptors contributes to the ischaemia-induced facilitation of glutamate release [252]. There is down-regulation of P2X1 receptor mRNA and upregulation of P2Y1 and P2Y2 receptors on smooth muscle in rat subarachnoid haemorrhage [516]. Nearly 50% of cerebral hypoxic hyperaemia was attenuated in A2A KO mice [517]. Reduced ATP levels occur in hypoxic brain and this has been claimed to be the basis of sympathetic transmission failure in the guinea-pig hippocampus during hypoxia [518]. Unlike other pathological conditions (e.g. ischaemic reperfusion injury, subarachnoid haemorrhage, hypertension and diabetes) that diminish endothelium-mediated dilation of cerebral arteries, severe traumatic brain injury enhanced the dilator sensitivity of endothelial P2Y receptors [519]. Treatment with adenosine receptor agonists have shown benefit in experimental CNS trauma and attenuated post-traumatic hypoperfusion [520]. Surprisingly, functional P2X receptormediated contraction of post-mortem human cerebral arteries remains for 37-54 hours after death [521]. Early papers showed release of adenosine from ischaemic brain [402,522,523] and it was shown to have a protective effect against ischaemic injury [524-526]. A1 receptor activation decreases cytotoxic amino acid release from both neurones and glial cells [527-529] and A2 receptor agonists are clinically viable for the treatment of ischaemic brain disorders [530]. However, adenosine, acting via A2A receptors, enhances glutamate release during ischaemia [531], while A2 receptor antagonists reduce ischaemic injury [532]. A2A receptor antagonists reduced brain injury in neonatal cerebral hypoxia-ischaemia [533-536]. A2A receptor deficiency also attenuates brain injury induced by transient focal ischaemia in mice [537], but a later study claimed that there was aggravated brain damage after hypoxic ischaemia in immature A2A

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KO mice [538]. Deletion of A1 receptors did not alter neuronal damage following ischaemia in vivo or in vitro [539]. A3 receptor agonists have also been shown to be protective against cerebral ischaemic damage [540-542]. Inosine, as well as adenosine, reduced astroglial injury in ischaemia and it was suggested that adenosine was acting after breakdown to inosine [543]. Adenosine inhibits striatal GABAergic transmission during in vitro ischaemia [544]. Short cerebral ischaemic preconditioning up-regulates A1 and A2B receptors in the hippocampal CA1 region of rats [545]. An increase in A1 receptor gene expression in cerebral ischaemia in rats has been reported [546]. The protective effects of A2A antagonists in brain ischaemia may be largely due to reduced glutamate outflow from neurones and glial cells [547]. Neurological deficit and ATP depletion occurs after focal ischaemia [548]. During brain ischaemia, tissue stores of ATP are depleted and released ATP is rapidly degraded to adenosine with subsequent release of excitotoxic amino acids leading to ischaemic damage [549]. Hydrolysis of ATP released during cerebral ischaemia is carried out by ATP diphosphohydrolase and 5'-nucleotidase; upregulation of these enzymatic activities leads to increased adenosine production [512,550]. Endothelial P2Y2 receptor-mediated dilations of rat middle cerebral artery to UTP were potentiated after ischaemia-reperfusion, while P2Y1 receptor-mediated dilation was attenuated after ischaemia-reperfusion [551]. Hypoxia-ischaemia and ATP release are associated with glial swelling and blebbing and this may play an important role in the pathogenesis of brain swelling [552]. More recent papers suggest that interference with P2 receptor-mediated events provides neuroprotection from brain ischaemia. For example, suramin reduces infarct volume in focal brain ischaemia in rats [553]. Upregulation of P2X2 receptors on neurones and P2X4 receptors on microglia was observed in ischaemic-injured hippocampus, which was prevented by P2 receptor antagonists [513]. Neuroprotective effects of the P2 receptor antagonist, pyridoxalphosphate-6azophenyl-2,4-disulfonic acid (PPADS) on focal cerebral ischaemia-induced injury in rats has been reported [511] and to accelerate recovery from hypoxic/hyperglycaemic perturbations of guinea-pig hippocampal neurotransmission [510]. Neuroprotection was also achieved by application of PPADS and suramin on hippocampal slice cultures subjected to oxygen and glucose deprivation [554]. Genetic deletion of P2X7 receptors (P2X7 KOs), or P2X7 receptor antagonists, did not affect cell death induced by cerebral ischaemia, suggesting that P2X7 receptors are not primary mediators of neuronal injury in ischaemia [515]. This view was not supported by experiments that showed upregulation of P2X7 receptors after ischaemia in the cerebral cortex of rats [354]. Supersensitivity of P2X7 receptors in cerebrocortical cell cultures after in vitro ischaemia has also been reported [514]. Reactive blue 2 reduced ischaemic brain damage, perhaps by acting on P2X7 receptors on reactive microglia [355]. Downregulation of P2X7 receptor expression in rat oligodendrocyte precursor cells occurs after hypoxic ischaemia [555]. Blockade of P2X receptors, accompanied by activation of GABAergic inhibition, protects against ischaemic neural cell death in the gerbil hippocampus [556]. Activation of P2X receptors and consequent Ca2+ influx might contribute to the


ischaemia-induced facilitation of glutamate release [252]. P2 receptor stimulation plays a deleterious role during severe ischaemic conditions in rat hippocampal slices [557]. Real time measurements of the release of purines during in vitro ischaemia in hippocampal slices suggest that ATP and adenosine, released during ischaemia, are to a large extent independent processes [558]. Cortical spreading depression releases ATP into the extracellular space and the subsequent activation of P2Y receptors makes a major contribution to the induction of ischaemic tolerance in the brain [559]. There is purinergic modulation, via A2A and P2X receptors and of glutamate release in ischaemic hippocampus [509]. Downregulation of hippocampal adenosine kinase after focal ischaemia appears to be an endogenous neuroprotective mechanism [560]. The diadenosine polyphosphate, Ap4A, also protects against injury induced by ischaemia in rat [561], probably via P2X receptors (see [562]). The transcription cofactor, LMO4, is a rapidly induced downstream effector of ATP signalling that promotes neurone survival following hypoxia [563]. Pretreatment with cerebrocrast, a 1,4dihydropyridine derivative, is claimed to prevent ischaemic brain damage and promote ATP production in brain cells [564]. In summary, A1 receptor agonists, while A2A and P2 receptor antagonists have protective effects against cerebral ischaemic injury. Neuroinflammatory Disorders Contrary to the earlier view that the brain is an immunologically privileged organ unable to mediate an inflammatory response, immuno-mediated reactions do occur in the brain. The CNS can undergo all the typical changes in inflammation, activate endogenous inflammatory cells and generate inflammatory mediators [565]. Neurones are surrounded by a dense population of support cells, astroglia, oligodendroglia and microglia, and biochemical information is exchanged between them. Microglia are immune cells and share all the roles of macrophages in the periphery. Indeed, microglia play a key protective role in CNS trauma and infections, but are also involved in regeneration and in CNS malfunction. Microglia release several factors that affect neural functions including cytokines, chemokines, growth factors, ATP and activated oxygen and nitrogen species. Purinergic signalling, involving ATP released from both neurones and glial cells and its breakdown product adenosine, appear to play a major role in the neuroimmune and neuroinflammatory events involving microglia [566,567], including neuropathic pain [568,569]. ATP potently activates nuclear factor of activated T cells, a central transcription factor involved in cytokine gene expression and may represent a novel mechanism by which extracellular ATP can modulate early inflammatory gene expression within the nervous and immune system [570]. A later paper suggests that P2X7 receptors mediate the phosphorylation of cAMP response-element binding protein, a putative inhibitory transcription factor in microglia, suggesting that ATP may be an endogenous inhibitor or neuroprotective molecule, decreasing the inflammatory capacity of microglia [571]. Microglia often need priming by proinflammatory factors such as IL-1, implicated in neurodegeneration, in order to


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generate a full response. Secretion of IL-1 is the end result of a complex chain of intracellular events occurring within a multi-molecular structure named the ‘inflammasome’ [572]. Inflammasome activation of IL-1 release is regulated by various factors, including extracellular ATP acting via P2X 7 receptors [573]. ATP also increases 2-arachidonoylglycerol (2-AG) production via P2X7 receptors on microglial cells and because prolonged increases in 2-AG levels in brain parenchyma are thought to orchestrate neuroinflammation. Microglial P2X7 receptors are activated by purines to release inflammatory cytokines such as IL-1, IL-6 and TNF- [574]. Activated microglia can also act as scavenger cells that induce apoptosis in damaged neurones by releasing toxic factors, including NO, and then take up the debris by phagocytosis [343,345]. The P2X7 receptor is involved in the formation of multinucleated giant macrophage-derived cells, a hallmark of chronic inflammatory reactions [575]. Lysophosphatidylcholine, an inflammatory phospholipid, may regulate microglial functions by enhancing the sensitivity of P2X7 receptors [576]. There has been a report that prion infection is associated with hypersensitivity of P2X7 receptors in microglia [577]. Expression of the P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain has also been reported [578]. Activation of microglial cells by pro-inflammatory bacterial lipopolysaccharide leads to a transient increase in ivermectin-sensitive P2X4 receptor currents, while dominant P2X7 receptor currents remain largely unaffected; both subtypes contribute to neuroinflammatory mechanisms and pathologies [579]. Astrocytes can sense the severity of damage in the CNS via ATP release from damaged cells and can modulate the TNF--mediated inflammatory response, depending on the extracellular ATP concentration and corresponding type of astrocyte P2 receptor activated [580]. Thus, micromolar ATP activation of P2Y receptors may act to boost a moderate inflammatory response, whereas millimolar ATP activation of P2X receptors may prevent the perpetuation of a comparatively large inflammatory response perhaps by induction of apoptosis. Protein kinase B/Akt is a key signalling molecule that regulates cell survival, growth and metabolism and inhibits apoptosis [581]. P2X7 receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 (MCP-1) expression via MAPK and it was suggested that regulation of MCP-1 in astrocytes by ATP may be important in mediating communication with haematopoietic inflammatory cells [327]. ATP hydrolysis is reduced in meningitis, involving inflammation, whereas hydrolysis of ADP and AMP is increased [582]. Neurodegenerative Diseases Parkinson’s Disease In Parkinson’s disease there is a progressive loss of dopaminergic neurones of the substantia nigra pars compacta projecting to the striatum. The dopamine precursor L-DOPA is still the most commonly prescribed treatment for Parkinson’s disease, but long-term treatment with L-DOPA often produces uncontrollable movements know as dyskinesia. While the focus has been on the role of adenosine A2A receptors and their interaction with dopamine receptors in


Parkinson’s disease (see [583]), P2 receptors have also been implicated. Release of ATP from disrupted cells may cause cell death in neighbouring cells expressing P2X7 receptors, leading to a necrotic volume increase, which has been proposed in the pathogenesis of Parkinson’s disease [584]. Differing expression patterns of different P2 receptor subtypes occurs in the dopaminergic system [585] and a facilitatory action by ATP and glutamate on taurines effect on osmolarity suggests that this could influence the nigral dopaminergic cell vulnerability in Parkinson's disease [586]. MPTP causes rapid induction of Parkinsonian symptoms in humans and primates through its toxicity on dopaminergic neurones. A recent study has shown that MPP+, the metabolite of MPTP, can induce ATP depletion in platelets and attenuate platelet aggregation, a feature of patients with Parkinson's disease. Alzheimer’s Disease ATP release during neuronal excitation or injury can enhance the inflammatory effects of cytokines and prostaglandin E2 in astrocytes and may contribute to the chronic inflammation seen in Alzheimer’s disease [587]. P2X7 receptors are upregulated in human Alzheimer’s diseased brains and in animal models [588,589]. Stimulation of P2X7 receptors on human macrophages and microglia enhanced the degenerative lesions observed in Alzheimer’s disease [590]. P2X7 receptors could therefore represent a therapeutic target for inflammatory responses seen in neurodegenerative disorders. Block of P2X7 receptor-mediated activity with BBG was shown to be neuroprotective in an animal model of Alzheimer's disease [591]. Activation of microglia by amyloid (A) requires P2X7 expression and it is suggested that A microglia stimulation may open up new avenues for the treatment of Alzheimer's disease [356]. The G51S purine nucleoside phosphorylase polymorphism is associated with a faster rate of cognitive decline in Alzheimer's, highlighting the important role of purine metabolism in the progression of the disease [592]. P2Y1 receptors are expressed on a number of structures that are characteristic of Alzheimer’s disease, such as neurofibrillary tangles, neurite plaques and neuropil threads [593], and P2Y2 receptor activation might mediate a neuroprotective effect [594]. Selective loss of P2Y2 receptor immunoreactivity in the parietal (but not occipital) cortex is associated with Alzheimer's disease neuropathology [595]. Oral administration of uridine, the precursor of UTP that acts on P2Y2 receptors, increases synaptic activities and it was suggested that this treatment may ameliorate some of the manifestations of Alzheimer's disease [596]. Abnormalities in calcium-mediated signal transduction triggered by ATP in microglia from Alzheimer’s disease patients have been reported [597]. Amyloid precursor protein and A regulate extracellular ATP levels in the brain, suggesting a novel mechanism in A-mediated Alzheimer's disease pathology [598]. A inhibits ATP release from deoxygenated erythrocytes, suggesting a role for vascular amyloid peptide in Alzheimer's disease [599]. Huntington’s Disease Changes in P2X receptor-mediated neurotransmission in cortico-striatal projections have been found in two different transgenic models of Huntington’s disease [600]. In a later

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paper from this group, in vivo data from a mouse model of Huntington's disease showed that altered P2X7 receptor level and function contributes to Huntington's disease pathogenesis and highlights the therapeutic potential of P2X7 receptor antagonists [600]. However, decrease in stimulated A1 and A2A receptors has also been implicated in Huntington's disease [601,602]. Amyotrophic Lateral Sclerosis (ALS) Potentiation of P2X4 receptors by the anti-parasitic medication ivermectin (22,23-dihydroavermectin B1a + 22,23dihydroavermectin B1b) extends the life span of the transgenic superoxide dismutase 1 (SOD1) mouse model of ALS [603]. Increased expression of P2X1 receptors on axotomized facial motoneurons was impaired in SOD1-G93A-mutant mice [604], perhaps due to the SOD1 mutation interfering with injury-elicited P2X1 activation. This finding suggests that the release of ATP from mutant motor neurones is altered after damage. P2X4 receptor immunoreactivity is selectively associated with degenerating neurones in transgenic rodent models of ALS [605]. Diabetic Neuropathies Diabetic neuropathy includes central neuropathic complications, such as decreased cognitive performance accompanied by modifications of hippocampal morphology and plasticity [606,607]. It has been shown that synaptic ATP signalling is depressed in streptozotocin-induced diabetic rats [608] and that the density of P2X3/6/7 and P2Y2/6/11 receptors is decreased in hippocampal nerve terminals compared with controls. Multiple Sclerosis As has been described in previous Sections, P2 receptors on oligodendrocytic progenitor cells regulate migration, proliferation and differentiation [388]. In multiple sclerotic lesions of autopsied brain tissue, P2X7 receptors were demonstrated on reactive astrocytes, whereas in cultured astrocytes P2X7 receptor stimulation increased the production of NOS activity [325]. Interferon- (IFN-) has beneficial effects in remitting/relapsing multiple sclerosis, perhaps by preventing astrocyte apoptosis; the levels of apyrase and 5’-nucleotidase increased in synaptosomes from the cerebral cortex of rats that were experimentally demyelinated with ethidium bromide and treated with IFN- [609], indicating that IFN- might interfere with the metabolism of purines. Neuronal pathology is an early feature of multiple sclerosis and its animal model of experimental autoimmune encephalomyelitis (EAE). Lesional accumulation of P2X receptors on macrophages in rat CNS during EAE has been described [610]. P2X7 expression is elevated in seemingly normal axon tracts in patients with multiple sclerosis and ATP can kill oligodendrocytes by activating P2X7 receptors. Mice deficient in P2X7 receptors are more susceptible to EAE than wild-type mice and show enhanced inflammation in the CNS [611]. The hydrolysis of ATP was modified in the serum and spinal cord membrane preparation of immunised rats and the observed changes correlated with clinical and histopathological manifestations of EAE [612]. NTPase1, an ectonucleotidase that degrades ATP to AMP, is expressed by immuno-suppressive regulatory T


cells (Treg) cells. Patients with the remitting/relapsing form of multiple sclerosis have strikingly reduced numbers of NTPDase1-positive Treg cells, suggesting that purines might be involved [613]. A regulatory role of P2Y1 receptor signalling in oligodendrocyte progenitor cells has been observed and it has been suggested that ATP released in high amounts under inflammatory conditions might act on P2Y1 receptors to influence the remyelination processes in multiple sclerosis [388]. P2Y12 receptor expression has also been identified in the lesioned cerebral cortex of multiple sclerosis patients [614]. Recently the P2Y-like GPR17 receptor has been suggested as a novel target to foster repair of demyelinating lesions that occur in multiple sclerosis [615]. Epileptic Seizures Epilepsy affects approximately 1% of the population worldwide and recurring seizures have devastating behavioural, social and occupational consequences, damaging the brain and increasing pre-existing neurological deficits. Current anticonvulsant drugs and complementary therapies are not sufficient to control seizures in about a third of epileptic patients, so there is an urgent need for treatments that prevent development and control epilepsy better. Epilepsy is often accompanied by massive glial cell proliferation, the role of these cells in seizures and epilepsy is still unclear. The focus has been on the role of adenosine (P1) receptors in epileptic seizures ([616]; see below). However, microinjection of ATP analogues into the prepiriform cortex induces generalized motor seizures suggesting that P2X receptor antagonists may have potential as neuroleptic agents [617]. Epileptiform activity in the CA3 region of rat hippocampal slices is modulated by adenine nucleotides, probably acting via an excitatory P2X receptor [618]. The hippocampus of chronic epileptic rats shows abnormal responses to ATP associated with increased expression of P2X7 receptors, which are substantially upregulated in chronic pilocarpineinduced epilepsy in rats (perhaps in microglia) and may participate in the pathophysiology of temporal lobe epilepsy [619]. In a study of kainate-provoked seizures, enhanced immunoreactivity of the P2X7 receptor was observed in microglia as they are changed from the resting to the activated state [620]. The amount of extracellular ATP detected in hippocampal slices following electrical stimulation of Schaffer collaterals was significantly greater in mice that have an inherited susceptibility to audiogenic seizures [621], this is perhaps associated with reduced brain Ca2+-ATPase activity. Uridine is released during epileptic activity and may act as an inhibitory neuromodulator [622], although the underlying mechanism is not known. Increased hydrolysis of ATP occurs in rat hippocampal slices after seizures induced by quinolinic acid [623]. There is a decrease of presynaptic P2X receptors in the hippocampus of rats that have suffered a convulsive period, which may be associated with the development of seizures and/or of neurodegeneration during epilepsy [624]. Release of glutamate from astrocytes by ATP has been implicated in epileptogenesis [293]. Increased P2X7 receptor expression in glial cells and glutamatergic nerve terminals in the hippocampus of temporal-lobe epilepsy induced by pilocarpine in rats has been reported [625]. They also showed a reduction in hippocampal P2X4 receptor im-


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munostaining in the chronic phase of epileptic seizures, perhaps reflecting decreased GABAergic signalling. Decreased activity of ectonucleotidases in epilepsy has been described (see [626]). However, it has been reported that treatment with antiepileptic drugs can modulate plastic events related to increase in nucleotide expression and activities in the pilocarpine model of epilepsy [627] and increases in nucleotide hydrolysis reported in patients with epilepsy [628]. In a model of status epilepticus induced by intraperitoneal kainate injections, there was increased expression of P2Y6 and P2Y12 and less so for P2X1, P2X4, P2X7 and P2Y13 receptors in hippocampal microglia after 48 hrs [629]. Neuropsychiatric Disorders Mood and Motivation: Depression and Anxiety Stimulation of P2Y1 receptors in the dorsomedial hypothalamus causes anxiolytic-like effects [116]. Chronically administered guanosine has anxiolytic effects in mice, perhaps associated with modulation of glutamatergic excitation [630], although receptors for guanosine have not been identified yet. There is evidence for a susceptibility locus on chromosome 10p15 in early onset obsessive-compulsive anxiety disorder, which involves nucleotide polymorphisms [631]. Major depressive illness is associated with significant elevation in the density of microglia and in circulatory levels of pro-inflammatory cytokines [632]. The P2X7 receptor gene has been shown to be involved in both major depressive illness [633-635] and bipolar affective disorders [636]. Electroconvulsive therapy is considered one of the most effective treatments for major depression [637]. The possibility that high levels of ATP are released with electroconvulsive therapy does not appear to have been considered (but see [637]). An antidepressant phenotype of P2X7 receptor KO mice has been described and it was suggested this is associated with immunological inflammatory, as well as neurological, changes in the CNS and that P2X7 receptor antagonists may represent a novel target for the treatment of depression [638]. Antidepressant drugs, such as fluoxetine and nortriptyline, decrease ectonucleotidase activity [639]. The prefrontal cortex is believed to play a major role in depression and suicidal behaviour and a recent study showed altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in this region of the brain [640]. Suramin blocked the conditioned fear response in a rat model, suggesting that P2 receptors might be involved in fear behaviour [641]. P2 receptors of the mesolimbicmesocortical system, probably of the P2Y1 subtype, are involved in the release of transmitters such as dopamine and glutamate, which are responsible for the generation and pattern of the behavioural outcome after motivation-related stimuli [118]. It has been claimed that P2Y1 receptors are involved in distinct cognitive functions after neonatal and adolescent prefrontal injury and may be important for psychomotoric deficits in adults. Schizophrenia The involvement of ATP receptors in schizophrenia has been discussed in relation to reports that antipsychotic drugs


such as haloperidol, chlorpromazine, and fluspirilene inhibit ATP-evoked responses mediated by P2X receptors [43]. It was suggested that ATP may have a facilitating role for dopaminergic neurones and that various antipsychotic drugs express their therapeutic effects by suppression of dopaminergic hyperactivity through inhibition of P2X receptormediated effects. Adenosine may also contribute to the pathophysiology of schizophrenia ([642] and see below). A hypothesis in which dysfunction of purinergic signalling (for example, decreased ATPase activity in erythrocytes, leading to increased levels of ATP and decreased adenosine) may lead to schizophrenia has been put forward [643]. Linkage studies in families with schizophrenia have identified a major linkage hotspot in the chromosome region 12q24.21-33 and the gene encoding the P2X7 receptor is located in the centre of this region. However, the P2X7 receptor was not found to be associated with schizophrenia in another study [644]. Antipsychotic drugs such as haloperidol, olanzapine and sulpiride, used for schizophrenia as well as mood-related psychotic symptoms, inhibit nucleotide hydrolysis in zebrafish brain membranes [645]. Bipolar Disorders The P2X7 receptor has been associated with bipolar disorder [636]. Chromosome 12q24.3 has been shown to be associated with bipolar disorder and shown to include the P2X7 receptor gene [646]. Alcohol and Drug Addiction Addiction is a chronic relapsing neurological disorder in which P2X and P2Y receptors have been implicated [4]. P2Y1 receptors were upregulated in both astrocytes and neurones in the striatum and nucleus accumbens of rats treated for 5 days with amphetamine [647]. Although ethanol is probably the oldest and most widely used psychoactive drug, the cellular mechanisms by which it affects the nervous system have been poorly understood. Some insights in relation to purinergic P2 receptor signalling have emerged in recent years [648]. Ethanol inhibits P2X receptor-mediated responses of dorsal root ganglion neurones by an allosteric mechanism. In the case of P2X4 receptors, ethanol inhibition is altered by mutation of histidine 241 in the rat. Furthermore, ethanol differentially affects ATP-gated P2X3 and P2X4 receptor subtypes expressed in Xenopus oocytes. Neuropathic Pain There is much current interest in the involvement of purinergic signalling in pain (see [119,649]). P2X3 receptors, probably those located on primary afferent nerve terminals in inner lamina II of the spinal cord, also have a significant role in neuropathic and inflammatory pain [650,651]. P2X2, P2X4 and P2X6 receptors have been located on dorsal horn neurones relaying nociceptive information further along the pain pathway [51]. In addition, ATP coreleased with GABA in spinal interneurones is probably involved in modulation of nociceptive pathways [652]. Importantly, it has been shown that P2X7 receptors in microglia are also involved in neuropathic pain. P2X receptor activation in the spinal cord may also elicit allodynia, with P2X4 receptor upregulation on spinal cord microglia playing a predominant role [653]. These observations have led to an explosion of work fo-

Burnstock et al.

cussed on purinergic signalling in neuropathic pain [649,654-656]. However, the underlying mechanisms involving both P2X4 and P2X7 receptors are still not clear [657,658]. Following the initial discovery by Tsuda et al. [653], there have been a number of papers investigating the role of P2X4 receptors on spinal microglia in neuropathic pain [655,657]. Brain-derived neurotrophic factor (BDNF) is released from microglia by the stimulation of P2X4 receptors by effecting anion reversal potentials in spinal lamina I neurones [659]. The involvement of increased spinal fibronectin following peripheral nerve injury in the upregulation of microglial P2X4 receptors has been considered [660]. Enhancement of pain behaviour after nerve injury not only requires the P2X receptor, but also phospho38 (p38) MAPK [661]. ATP causes the activation of p38 or ERK1/2, MAPKs resulting in the release of TNF- and IL-6. In rats displaying allodynia, the level of p38 was increased in microglia. Intraspinal administration of the p38 inhibitor, SB203580, suppressed allodynia, suggesting that neuropathic pain hypersensitivity depends on the activation of the p38 signalling pathway in microglia in the dorsal horn following peripheral nerve injury. Platelet activating factor, which is released from activated microglia, is a potent inducer of tactile allodynia and thermal hyperalgesia after intrathecal injection into the spinal cord and it was suggested that this response is mediated by ATP [662]. The P2X7 receptor, via regulation of IL-1 production, also plays a common upstream transductional role in the development of neuropathic and inflammatory pain [663]. Data from P2X4 and P2X7 receptor KO animals share a common pain phenotype, although this phenotype appears to be conferred via different mechanisms [664]. In contrast to P2X receptors, activation of UTP-sensitive P2Y2 and/or P2Y4 receptors and the UDP-sensitive P2Y 6 receptor, produces inhibition of spinal pain transmission [665]. P2Y1 and P2Y4 receptors were identified in sensory neurones, in a subpopulation of which P2X 3 receptors were also expressed [666]. P2Y receptors are involved in the sensory ganglia, neurones in the dorsal spinal cord and in glial cells [667]. The rostral ventromedial medulla serves as a critical link in bulbo-spinal nociceptive modulation and it has been suggested that while on-cells preferentially express P2X receptors, off-cells express P2Y receptors in this region [668]. Activation of P2Y receptors inhibits P2X3 receptor channels via G protein-dependent facilitation of their desensitisation [669]. A number of studies have demonstrated the therapeutic potential of modulating specific P2X receptor subtypes to treat neuropathic pain. Intrathecal administration of ATP produces long-lasting allodynia, most likely via P2X2/3 receptors [670]. The involvement of spinal P2X2 and P2X3 receptors in neuropathic pain in a mouse model of chronic constriction injury has been claimed [671]. A recent study suggests that P2X 3/P2X2/3 receptor-dependent cytosolic phospholipase A2 (cPLA2) activity in primary sensory neurones is a key event in neuropathic pain and that cPLA 2 might also be a potential target for treating neuropathic pain [672]. It is claimed that sensitisation of P2X3 receptors rather than a change in ATP release is responsible for neuropathic


pain and allodynia [673]. Data has been presented to suggest that the P2X3 and P2X2/3 receptor antagonism that reduces inflammatory hyperalgesia and chemogenic nociception is mediated by the spinal opioid system [674]. As neuropathic pain and allodynia are abolished in both P2X4 and P2X7 knockout mice, there is great interest in finding selective antagonists that might be suitable for therapeutic development. Recent reviews on the role of P2X7 receptors in pain and inflammation highlight the potential therapeutic benefit of P2X7 receptor modulation [675,676]. Antidepressants have been shown to be effective in relieving neuropathic pain [677] and preliminary clinical studies with paroxetine, which antagonises P2X4 receptors in transfected cells, suggest that it is effective against chronic pain. Migraine The involvement of ATP in migraine was first suspected in conjunction with the vascular theory of this disorder with ATP released from endothelial cells during reactive hyperaemia associated with pain following cerebral vascular vasospasm (that is not associated with pain) [678]. More recently, P2X3 receptor involvement in neuronal dysfunction in brain areas that mediate nociception such as the trigeminal nucleus and thalamus have been considered [679-681]. P2X3 receptors are the only ligand-gated channel known to be expressed exclusively by a subset of trigeminal and spinal sensory neurones [682]. The interaction of P2Y1 receptors on trigeminal neurones with P2X3 receptors after sensitization of these neurones with algogenic stimuli (e.g., NGF, BDNF or bradykinin) has been proposed and may also represent a new potential target for antimigraine drugs [683]. Slow upregulation of nociceptive P2X3 receptors on trigeminal neurones by calcitonin gene-related peptide (CGRP) has been demonstrated [680]. In an in vivo model of mouse trigeminal pain, anti-NGF treatment suppressed responses evoked by P2X3 receptor activation [684]. However, the effect of adding NGF on P2X3 receptor-mediated currents was shown not to be mediated by NGF-induced CGRP release.


993

There is also a growing recognition of the roles of ectonucleotidases in both healthy and pathological tissues. Development of ecto-nucleotidase inhibitors is an important target; a start has been made [690], and the availability of some of the relevant KO animals has already proven the importance of this approach. A major advance was made recently when the crystal structures of P2X4 and A2A receptors were described [691,692]. It is highly desirable for this to be followed by research into the crystal structure of other nucleoside and nucleotide receptor subtypes. Many cell types in the body express multiple receptors for purines and pyrimidines (see [62]). This poses important questions about their different short- and long-term signalling roles in healthy and pathological conditions, how they interact with each other and with receptors for other signalling molecules. Purinergic signalling is still in its infancy, on the steep slope of the growth curve, and there is still much to be discovered. ACKNOWLEDGEMENTS The authors declare that there are no conflicts of interest. The authors thank Dr Gillian E. Knight for excellent editorial assistance. AV was supported by Alzheimer’s Research Trust (UK), National Institute of Health (NIH), Grant Agency of the Czech Republic (grants GACR 309/08/1381 and GACR 305/08/1384). ABBREVIATIONS 2-AG

=

2-Arachidonoylglycerol

,-meATP

=

,-Methylene ATP

A

=

Amyloid

Ach

=

Acetylcholine

ADP

=

Adenosine diphosphate

FUTURE CHALLENGES

ALS

=

Amyotrophic lateral sclerosis

A number of selective antagonists to receptor subtypes of nucleoside and nucleotide receptors have been identified which are useful tools for in vitro studies (see [4]). In the case of the four adenosine receptors there are agonists and antagonists that can be used in in vivo studies. However, there is an urgent need for medicinal chemists to develop simple molecules that are orally bioavailable, stable in vivo and, when appropriate, cross the blood-brain barrier, to be used to explore the therapeutic potential of purinergic signalling. A start has been made with P2X1, P2X3 and P2X2/3 receptor antagonists and also with P2X7 receptor antagonists (see [685-688]).

ATP

=

Adenosine 5’-triphosphate

BBG

=

Brilliant blue G

BDNF

=

Brain-derived neurotrophic factor

BzATP

=

2’-&3’-O-(4-benzoyl-benzoyl)-ATP

cAMP

=

Cyclic adenosine monophosphate

CGRP

=

Calcitonin gene-related peptide

CNS

=

Central nervous system

COX

=

Cyclooxygenase 2

cPLA2

=

Cytosolic phospholipase A2

CREB

=

cAMP responsive element binding protein

EAE

=

Experimental autoimmune encephalomyelitis

EPSC

=

Excitatory postsynaptic current

ER

=

Endoplasmic reticulum

There is much current discussion about the mechanisms of ATP transport across plasma membranes (see [689]). The development of drugs that enhance or reduce ATP release from cells would be a valuable priority. We anticipate that given the multiplicity of mechanisms involved such drugs could prove to exhibit some degree of selectivity.


Burnstock et al.

GABA

=

-Aminobutyric acid

[7]

GL

=

Glia limitans

[8]

GSK-3

=

Glycogen synthase kinase-3

[9]

IEG

=

Immediate early genes

IFN-

=

Interferon-

[10]

IL6

=

Interleukin-6

[11]

InsP3

=

Inositol trisphosphate

KO

=

Knock out

L-DOPA

=

L-3,4-dihydroxyphenylalanine

LTD

=

Long-term depression

LTP

=

Long-term potentiation

[14]

MAPK

=

Mitogen-activated protein kinase

[15]

MCP-1

=

Monocyte chemoattractant protein-1

MPTP

=

1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine

NA

=

Noradrenaline

NGF

=

Nerve growth factor

NMDA

=

N-methyl-D-aspartate

NO

=

Nitric oxide

oxATP

=

Oxidised ATP

p38

=

Phospho38

PDE

=

Phosphodiesterase

PLC

=

Phospholipase C

[21]

PPADS

=

Pyridoxalphosphate-6-azophenyl-2,4disulfonic acid

[22]

SOD1

=

Superoxide dismutase 1

STAT3

=

Signal transducer and activator of transcription 3

TNF-

=

Tumour necrosis factor-

Treg

=

Regulatory T cells

TRP

=

Transient receptor potential

UDP

=

Uridine diphosphate

UTP

=

Uridine 5’-triphosphate

VNUT

=

Vesicular nucleotide transporter

REFERENCES [1] [2] [3]

[4] [5] [6]

Burnstock, G. Purinergic nerves. Pharmacol. Rev., 1972, 24, 509581. Burnstock, G. Do some nerve cells release more than one transmitter? Neuroscience, 1976, 1, 239-248. Abbracchio, M. P.; Burnstock, G.; Verkhratsky, A.; Zimmermann, H. Purinergic signalling in the nervous system: an overview. Trends Neurosci., 2009, 32, 19-29. Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev., 2007, 87, 659-797. North, R. A.; Verkhratsky, A. Purinergic transmission in the central nervous system. Pflugers Arch., 2006, 452, 479-485. Verkhratsky, A.; Krishtal, O. A.; Burnstock, G. Purinoceptors on neuroglia. Mol. NeuroBiol., 2009, 39, 190-208.

[12] [13]

[16] [17] [18]

[19]

[20]

[23]

[24] [25]

[26] [27]

[28]

[29] [30]

[31]

Abbracchio, M. P.; Burnstock, G. Purinergic signalling: pathophysiological roles. Jpn. J. Pharmacol., 1998, 78, 113-145. Zimmermann, H. Nucleotide signaling in nervous system development. Pflugers Arch., 2006, 452, 573-588. Burnstock, G.; Verkhratsky, A. Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis., 2010, 1, e9. Burnstock, G. Purinergic receptors. J. Theor. Biol., 1976, 62, 491503. Burnstock, G. A basis for distinguishing two types of purinergic receptor. In: Cell. membranhe receptors for drugs and hormones: A multidisciplinary approach. Eds., Straub, R. W.; Boils, L. Raven Press, New York. 1978, pp 107-118. Londos, C.; Cooper, D. M.; Wolff. J. Subclasses of external adenosine receptors. Proc. Natl. Acad. Sci. USA, 1980, 77, 2551-2554. van Calker, D.; Muller, M.; Hamprecht, B. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J. Neurochem., 1979, 33, 999-1005. Burnstock, G.; Kennedy, C. Is there a basis for distinguishing two types of P2-purinoceptor? Gen. Pharmacol., 1985, 16, 433-440. Abbracchio, M. P.; Burnstock, G. Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol. Ther., 1994, 64, 445475. Dubyak, G. R. Signal transduction by P2-purinergic receptors for extracellular ATP, Am. J. Respir. Cell. Mol. Biol. 1991, 4, 295-300. Brake, A. J.; Wagenbach, M. J.; Julius, D. New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor. Nature, 1994, 371, 519-523. Lustig, K. D.; Shiau, A. K.; Brake, A. J.; Julius, D. Expression cloning of an ATP receptor from mouse neuroblastoma cells. Proc. Natl. Acad. Sci. USA, 1993, 90, 5113-5117. Valera, S.; Hussy, N.; Evans, R. J.; Adami, N.; North, R. A.; Surprenant, A.; Buell, G. A new class of ligand-gated ion channel defined by P2x receptor for extracellular ATP. Nature, 1994, 371, 516-519. Webb, T. E.; Simon, J.; Krishek, B. J.; Bateson, A. N.; Smart, T. G.; King, B. F.; Burnstock, G.; Barnard, E. A. Cloning and functional expression of a brain G-protein-coupled ATP receptor. FEBS Lett., 1993, 324, 219-225. Burnstock, G. Purine and pyrimidine receptors. Cell. Mol. Life Sci., 2007, 64, 1471-1483. Pankratov, Y.; Lalo, U.; Verkhratsky, A.; North, R. A. Quantal release of ATP in mouse cortex. J. Gen. Physiol., 2007, 129, 257265. Pankratov, Y.; Lalo, U.; Verkhratsky, A.; North, R. A. Vesicular release of ATP at central synapses, Pflugers Arch., 2006, 452, 589597. Bowser, D. N.; Khakh, B. S. Vesicular ATP is the predominant cause of intercellular calcium waves in astrocytes. J. Gen. Physiol., 2007, 129, 485-491. Zhang, Z.; Chen, G.; Zhou, W.; Song, A.; Xu, T.; Luo, Q.; Wang, W.; Gu, X. S.; Duan, S. Regulated ATP release from astrocytes through lysosome exocytosis. Nat. Cell. Biol., 2007, 9, 945-953. Dubyak, G. R. ATP release mechanisms. In: Nucleotides and Regulation of Bone Cell. Function Eds. Burnstock, G.;. Arnet, T. R. Taylor & Francis Group, Boca Raton, Florida. 2006, .pp 99-158. Cotrina, M. L.; Lin, J. H.; Alves-Rodrigues, A.; Liu, S.; Li, J.; Azmi-Ghadimi, H.; Kang, J.; Naus, C. C.; Nedergaard, M. Connexins regulate calcium signaling by controlling ATP release. Proc. Natl. Acad. Sci. USA, 1998, 95, 15735-15740. Scemes, E.; Suadicani, S. O.; Dahl, G.; Spray, D. C. Connexin and pannexin mediated cell-Cell. communication. Neuron Glia Biol., 2007, 3, 199-208. Zimmermann, H. Ectonucleotidases in the nervous system, Novartis Found. Symp. 2006, 276, 113-128; discussion 128-130, 233-117, 275-181. Wall, M. J.; Dale, N. Auto-inhibition of rat parallel fibre-Purkinje Cell. synapses by activity-dependent adenosine release. J. Physiol., 2007, 581, 553-565. Phillis, J. W.; Edstrom, J. P.; Kostopoulos, G. K.; Kirkpatrick, J. R. In: Role of Adenosine and Adenine Nucleotides in Central Nervous Function. physiological and regulatory functions of adenosine and adenine nucleotides Eds. Baer, H. P.; Drummond, G. I. Raven Press, New York. 1979, pp 343-359.

Purinoceptors in the Brain [32]

[33] [34] [35]

[36]

[37]

[38] [39]

[40] [41]

[42] [43] [44]

[45]

[46] [47] [48] [49]

[50] [51]

[52]

[53]

[54]

[55]

Phillis, J. W.; Wu, P. H. The role of adenosine and its nucleotides in central synaptic transmission, Prog. NeuroBiol., 1981, 16, 187239. Williams, M. (1984) Mammalian central adenosine receptors. In: Handbook of Neurochemistry (ed. A. Lajtha), pp 1-25. Plenum Publishing Corporation, New York. Dunwiddie, T. V. The physiological role of adenosine in the central nervous system. Int. Rev. Neurobiol., 1985, 27, 63-139. Fredholm, B. B. Release of adenosine-like material from isolated perfused dog adipose tissue following sympathetic nerve stimulation and its inhibition by adrenergic alpha-receptor blockade. Acta Physiol. Scand, 1976, 96, 122-130. Fredholm, B. B.; IJzerman, A. P.; Jacobson, K. A.; Klotz, K. N.; Linden. J. International Union of Pharmacol.ogy. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev., 2001, 53, 527-552. Latini, S.; Pedata, F. Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J. Neurochem., 2001, 79, 463-484. Snyder, S. H. Adenosine as a neuromodulator, Annu. Rev. Neurosci., 1985, 8, 103-124. Bo, X.; Burnstock, G. Distribution of [3H]a,b-methylene ATP binding sites in rat brain and spinal cord. Neuroreport., 1994, 5, 1601-1604. Burnstock, G. (Guest Editor). Purinergic Neurotransmission. Semin. Neurosci., 1996, 8, 171-257. Burnstock, G. In: Purinergic Receptors in the Nervous System. Current Topics in Membranes. purinergic receptors and signalling Ed. Schwiebert, E. M. Academic Press, San Diego. 2003, PP 307368. Gibb, A. J.; Halliday, F. C. Fast purinergic transmission in the central nervous system. Semin. Neurosci., 1996, 8, 225-232. Inoue, K.; Koizumi, S.; Ueno, S. Implication of ATP receptors in brain functions. Prog. NeuroBiol., 1996, 50, 483-492. Abbracchio, M. P. ATP in brain function. In: Purinergic Approaches in Experimental Therapeutics. Eds. Jacobson, K. A.; Jarvis. M. F. Wiley-Liss, New York. 1997, pp 383-404 Masino, S. A.; Dunwiddie, T. V. Role of purines and pyrimidines in the central nervous system. In: Handbook of Experimental Pharmacol.ogy. Purinergic and Pyrimidinergic Signalling I - Molecular, Nervous and Urinogenitary System Function Eds. Abbracchio, M. P.; Williams, M. 2001, PP 251-288. Springer-Verlag, Berlin. Illes, P.; Alexandre Ribeiro. J. Molecular physiology of P2 receptors in the central nervous system. Eur. J. Pharmacol., 2004, 483, 5-17. Robertson, S. J.; Ennion, S. J.; Evans, R. J.; Edwards, F. A. Synaptic P2X receptors. Curr. Opin NeuroBiol., 2001, 11, 378-386. Khakh, B. S. Molecular physiology of P2X receptors and ATP signalling at synapses. Nat. Rev. Neurosci., 2001, 2, 165-174. Pankratov, Y.; Lalo, U.; Krishtal, O. A.; Verkhratsky, A. P2X receptors and synaptic plasticity. Neuroscience, 2009, 158, 137148. Edwards, F. A.; Gibb, A. J.; Colquhoun, D. ATP receptor-mediated synaptic currents in the central nervous system. Nature, 1992, 359, 144-147. Bardoni, R.; Goldstein, P. A.; Lee, C. J.; Gu, J. G.; MacDermott, A. B. ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J. Neurosci., 1997, 17, 52975304. Nieber, K.; Poelchen, W.; Illes, P. Role of ATP in fast excitatory synaptic potentials in locus coeruleus neurones of the rat. Br. J. Pharmacol., 1997, 122, 423-430. Pankratov, Y.; Castro, E.; Miras-Portugal, M. T.; Krishtal, O. A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus. Eur. J. Neurosci., 1998, 10, 3898-3902. Mori, M.; Heuss, C.; Gahwiler, B. H.; Gerber, U. Fast synaptic transmission mediated by P2X receptors in CA3 pyramidal cells of rat hippocampal slice cultuRes. J. Physiol. London, 2001, 535, 115123. Pankratov, Y.; Lalo, U.; Krishtal, O.; Verkhratsky, A. Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex. J. Physiol. 2002, 542, 529-536.

Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 8 [56]

[57] [58]

[59]

[60] [61]

[62]

[63]

[64] [65]

[66]

[67]

[68] [69]

[70]

[71] [72]

[73]

[74] [75] [76] [77]

[78]

995

Pankratov, Y.; Lalo, U.; Krishtal, O.; Verkhratsky, A. P2X receptor-mediated excitatory synaptic currents in somatosensory cortex. Mol. Cell. Neurosci., 2003, 24, 842-849. Cunha, R. A.; Ribeiro, J. A. ATP as a presynaptic modulator, Life Sci., 2000, 68, 119-137. Kato, F.; Kawamura, M.; Shigetomi, E.; Tanaka, J.; Inoue, K. ATPand adenosine-mediated signaling in the central nervous system: synaptic purinoceptors: the stage for ATP to play its "dual-role". J. Pharmacol. Sci., 2004, 94, 107-111. Matsuoka, I.; Ohkubo, S. ATP- and adenosine-mediated signaling in the central nervous system: adenosine receptor activation by ATP through rapid and localized generation of adenosine by ectonucleotidases. J. Pharmacol. Sci., 2004, 94, 95-99. Kogure, K.; Alonso, O. F. A pictorial representation of endogenous brain ATP by a bioluminescent method. Brain Res., 1978, 154, 273-284. Kukulski, F.; Sevigny, J.; Komoszynski, M. Comparative hydrolysis of extracellular adenine nucleotides and adenosine in synaptic membranes from porcine brain cortex, hippocampus, cerebellum and medulla oblongata. Brain Res., 2004, 1030, 49-56. Burnstock, G.; Knight, G. E. Cellular distribution and functions of P2 receptor subtypes in different systems. Int. Rev. Cytol., 2004, 240, 31-304. Kanjhan, R.; Housley, G. D.; Burton, L. D.; Christie, D. L.; Kippenberger, A.; Thorne, P. R.; Luo, L.; Ryan, A. F. Distribution of the P2X2 receptor subunit of the ATP-gated ion channels in the rat central nervous system. J. Comp Neurol., 1999, 407, 11-32. Loesch, A.; Burnstock, G. Electron-immunocytochemical localization of P2X1 receptors in the rat cerebellum. Cell. Tissue Res., 1998, 294, 253-260. Rubio, M. E.; Soto, F. Distinct Localization of P2X receptors at excitatory postsynaptic specializations. J. Neurosci., 2001, 21, 641653. Moore, D.; Chambers, J.; Waldvogel, H.; Faull, R.; Emson, P. Regional and cellular distribution of the P2Y1 purinergic receptor in the human brain: striking neuronal localisation. J. Comp Neurol., 2000, 421, 374-384. Moran-Jimenez, M. J.; Matute, C. Immunohistochemical localization of the P2Y1 purinergic receptor in neurons and glial cells of the central nervous system. Brain Res. Mol. Brain Res., 2000, 78, 5058. Neary, J. T.; Zimmermann, H. Trophic functions of nucleotides in the central nervous system. Trends Neurosci., 2009, 32, 189-198. Rathbone, M. P.; Middlemiss, P. J.; Gysbers, J. W.; Andrew, C.; Herman, M. A.; Reed, J. K.; Ciccarelli, R.; Di Iorio, P.; Caciagli, F. Trophic effects of purines in neurons and glial cells, Prog. NeuroBiol., 1999, 59, 663-690. Lakshmi, S.; Joshi, P. G. Activation of Src/kinase/phospholipase C/mitogen-activated protein kinase and induction of neurite expression by ATP, independent of nerve growth factor. Neuroscience, 2006, 141, 179-189. Burnstock, G. Purinergic cotransmission. Exp. Physiol., 2009, 94, 20-24. Barberis, C.; McIlwain, H. 5'-Adenine mononucleotides in synaptosomal preparations from guinea pig neocortex: their change on incubation, superfusion and stimulation. J. Neurochem., 1976, 26, 1015-1021. Sperlagh, B.; Sershen, H.; Lajtha, A.; Vizi, E. S. Co-release of endogenous ATP and [3H]noradrenaline from rat hypothalamic slices: origin and modulation by alpha2-adrenoceptors. Neuroscience, 1998, 82, 511-520. White, T. D. Direct detection of depolarisation-induced release of ATP from a synaptosomal preparation. Nature, 1977, 267, 67-68. Potter, P.; White, T. D. Release of adenosine 5'-triphosphate from synaptosomes from different regions of rat brain. Neuroscience, 1980, 5, 1351-1356. Richardson, P. J.; Brown, S. J. ATP release from affinity-purified rat cholinergic nerve terminals. J. Neurochem., 1987, 48, 622-630. Poelchen, W.; Sieler, D.; Wirkner, K.; Illes, P. Co-transmitter function of ATP in central catecholaminergic neurons of the rat. Neuroscience, 2001, 102, 593-602. Buller, K. M.; Khanna, S.; Sibbald, J. R.; Day, T. A. Central noradrenergic neurons signal via ATP to elicit vasopressin responses to haemorrhage. Neuroscience, 1996, 73, 637-642.

996 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 8 [79]

[80] [81]

[82] [83]

[84]

[85]

[86]

[87] [88] [89] [90]

[91] [92]

[93]

[94] [95]

[96]

[97] [98]

[99] [100] [101]

Kapoor, J. R.; Sladek, C. D. Purinergic and adrenergic agonists synergize in stimulating vasopressin and oxytocin release. J. Neurosci., 2000, 20, 8868-8875. Perez, M. T.; Bruun, A. Colocalization of (3H)-adenosine accumulation and GABA immunoreactivity in the chicken and rabbit retinas. Histochemistry, 1987, 87, 413-417. Jo, Y. H.; Role, L. W. Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons. J. Neurosci., 2002, 22, 4794-4804. Illes, P.; Wirkner, K.; Nörenberg, W.; Masino, S. A.; Dunwiddie, T. V. Interaction between the transmitters ATP and glutamate in the central nervous system. Drug Dev.. Res., 2001, 52, 76-82. Fujii, S.; Sasaki, H.; Mikoshiba, K.; Kuroda, Y.; Yamazaki, Y.; Mostafa Taufiq, A.; Kato, H. A chemical LTP induced by coactivation of metabotropic and N-methyl-D-aspartate glutamate receptors in hippocampal CA1 neurons. Brain Res., 2004, 999, 2028. Diaz-Hernandez, M.; Pintor, J.; Castro, E.; Miras-Portugal, M. T. Co-localisation of functional nicotinic and ionotropic nucleotide receptors in isolated cholinergic synaptic terminals. Neuropharmacoogy, 2002, 42, 20-33. Khakh, B. S.; Fisher, J. A.; Nashmi, R.; Bowser, D. N.; Lester, H. A. An angstrom scale interaction between plasma membrane ATPgated P2X2 and a4b2 nicotinic channels measured with fluorescence resonance energy transfer and total internal reflection fluorescence microscopy. J. Neurosci., 2005, 25, 6911-6920. Krugel, U.; Kittner, H.; Franke, H.; Illes, P. Purinergic modulation of neuronal activity in the mesolimbic dopaminergic system in vivo, Synapse, 2003, 47, 134-142. Parpura, V.; Zorec, R. Gliotransmission: Exocytotic release from astrocytes. Brain Res. Rev., 2009. Verkhratsky, A. Calcium ions and integration in neural circuits. Acta Physiol., (Oxf) 2006, 187, 357-369. Verkhratsky, A.; Toescu, E. C. Neuronal-glial networks as substrate for CNS integration. J. Cell. Mol. Med., 2006, 10, 826-836. Nishizaki, T. ATP- and adenosine-mediated signaling in the central nervous system: adenosine stimulates glutamate release from astrocytes via A2a adenosine receptors. J. Pharmacol. Sci., 2004, 94, 100-102. Wittendorp, M. C.; Boddeke, H. W.; Biber, K. Adenosine A3 receptor-induced CCL2 synthesis in cultured mouse astrocytes. Glia, 2004, 46, 410-418. Carrasquero, L. M.; Delicado, E. G.; Jimenez, A. I.; Perez-Sen, R.; Miras-Portugal, M. T. Cerebellar astrocytes co-express several ADP receptors. Presence of functional P2Y13-like receptors. Purinergic Signal., 2005, 1, 153-159. Wink, M. R.; Braganhol, E.; Tamajusuku, A. S.; Lenz, G.; Zerbini, L. F.; Libermann, T. A.; Sevigny, J.; Battastini, A. M.; Robson, S. C. Nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) is the dominant ectonucleotidase expressed by rat astrocytes. Neuroscience, 2006, 138, 421-432. Cotrina, M. L.; Lin, J. H.; Lopez-Garcia, J. C.; Naus, C. C.; Nedergaard, M. ATP-mediated glia signaling. J. Neurosci., 2000, 20, 2835-2844. Neary, J. T.; Rathbone, M. P.; Cattabeni, F.; Abbracchio, M. P.; Burnstock, G. Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells. Trends Neurosci., 1996, 19, 13-18. Mishra, S. K.; Braun, N.; Shukla, V.; Fullgrabe, M.; Schomerus, C.; Korf, H. W.; Gachet, C.; Ikehara, Y.; Sevigny, J.; Robson, S. C.; Zimmermann, H. Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation, Development, 2006, 133, 675-684. Stout, C. E.; Costantin, J. L.; Naus, C. C.; Charles, A. C. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J. Biol. Chem., 2002, 277, 10482-10488. Coco, S.; Calegari, F.; Pravettoni, E.; Pozzi, D.; Taverna, E.; Rosa, P.; Matteoli, M.; Verderio, C. Storage and release of ATP from astrocytes in culture. J. Biol. Chem., 2003, 278, 1354-1362. Montana, V.; Malarkey, E. B.; Verderio, C.; Matteoli, M.; Parpura, V. Vesicular transmitter release from astrocytes. Glia, 2006, 54, 700-715. Duan, S.; Neary, J. T. P2X7 receptors: properties and relevance to CNS function. Glia, 2006, 54, 738-746. Ballerini, P.; Di Iorio, P.; Caciagli, F.; Rathbone, M. P.; Jiang, S.; Nargi, E.; Buccella, S.; Giuliani, P.; D'Alimonte, I.; Fischione, G.;

Burnstock et al.

[102]

[103] [104] [105] [106]

[107] [108]

[109]

[110] [111]

[112]

[113]

[114] [115]

[116]

[117]

[118] [119] [120]

[121]

[122] [123]

Masciulli, A.; Romano, S.; Ciccarelli, R. P2Y2 receptor upregulation induced by guanosine or UTP in rat brain cultured astrocytes. Int. J. Immunopathol. Pharmacol., 2006, 19, 293-308. Paemeleire, K.; Leybaert, L. ATP-dependent astrocyte-endothelial calcium signaling following mechanical damage to a single astrocyte in astrocyte-endothelial co-cultuRes. J. Neurotrauma, 2000, 17, 345-358. Simard, M.; Arcuino, G.; Takano, T.; Liu, Q. S.; Nedergaard, M. Signaling at the gliovascular interface. J. Neurosci., 2003, 23, 9254-9262. Fields, R. D.; Burnstock, G. Purinergic signalling in neuron-glia interactions. Nat. Rev. Neurosci., 2006, 7, 423-436. Heneka, M. T.; Rodriguez, J. J.; Verkhratsky, A. Neuroglia in neurodegeneration. Brain Res. Rev., 2010, 63, 189-211. Nedergaard, M.; Rodriguez, J. J.; Verkhratsky, A. Glial calcium and diseases of the nervous system. Cell Calcium, 2009, 47, 140149. Wieraszko, A.; Ehrlich, Y. H. On the role of extracellular ATP in the induction of long-term potentiation in the hippocampus. J. Neurochem., 1994, 63, 1731-1738. Cunha, R. A.; Vizi, E. S.; Ribeiro, J. A.; Sebastiao, A. M. Preferential release of ATP and its extracellular catabolism as a source of adenosine upon high- but not low-frequency stimulation of rat hippocampal slices. J. Neurochem., 1996, 67, 2180-2187. Basheer, R.; Strecker, R. E.; Thakkar, M. M.; McCarley, R. W. Adenosine and sleep-wake regulation, Prog. NeuroBiol., 2004, 73, 379-396. Krueger, J. M.; Rector, D. M.; Roy, S.; Van Dongen, H. P.; Belenky, G.; Panksepp. J. Sleep as a fundamental property of neuronal assemblies. Nat. Rev. Neurosci., 2008, 9, 910-919. Antoniou, K.; Papadopoulou-Daifoti, Z.; Hyphantis, T.; Papathanasiou, G.; Bekris, E.; Marselos, M.; Panlilio, L.; Muller, C. E.; Goldberg, S. R.; Ferre, S. A detailed Behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors, Psychopharmacology, (Berl) 2005, 183, 154-162. Barraco, R. A.; Coffin, V. L.; Altman, H. J.; Phillis, J. W. Central effects of adenosine analogs on locomotor activity in mice and antagonism of caffeine. Brain Res., 1983, 272, 392-395. Kuzmin, A.; Johansson, B.; Gimenez, L.; Ogren, S. O.; Fredholm, B. B. Combination of adenosine A1 and A2A receptor blocking agents induces caffeine-like locomotor stimulation in mice. Eur. Neuropsychopharmacol., 2006, 16, 129-136. Levine, A. S.; Morley, J. E. Purinergic regulation of food intake. Science, 1982, 217, 77-79. Nagel, J.; Schladebach, H.; Koch, M.; Schwienbacher, I.; Muller, C. E.; Hauber, W. Effects of an adenosine A2A receptor blockade in the nucleus accumbens on locomotion, feeding, and prepulse inhibition in rats, Synapse, 2003, 49, 279-286. Kittner, H.; Franke, H.; Harsch, J. I.; El-Ashmawy, I. M.; Seidel, B.; Krugel, U.; Illes, P. Enhanced food intake after stimulation of hypothalamic P2Y1 receptors in rats: modulation of feeding Behav.iour by extracellular nucleotides. Eur. J. Neurosci., 2006, 24, 2049-2056. Williams, M. In: Purinergic receptors and central nervous system function.. PsychoPharmacology. The Third Generation of Progress Eds. Meltzer H. Y. Raven Press, New York. 1987, PP 289-301 Krugel, U.; Spies, O.; Regenthal, R.; Illes, P.; Kittner, H. P2 receptors are involved in the mediation of motivation-related Behavior. Purinergic Signal., 2004, 1, 21-29. Burnstock, G. Purinergic signalling and disorders of the central nervous system. Nat. Rev. Drug Discov., 2008, 7, 575-590. Maenhaut, C.; Van Sande, J.; Libert, F.; Abramowicz, M.; Parmentier, M.; Vanderhaegen, J. J.; Dumont, J. E.; Vassart, G.; Schiffmann, S. RDC8 codes for an adenosine A2 receptor with physiological constitutive activity. Biochem. Biophys. Res. Commun., 1990, 173, 1169-1178. Libert, F.; Schiffmann, S. N.; Lefort, A.; Parmentier, M.; Gerard, C.; Dumont, J. E.; Vanderhaeghen, J. J.; Vassart, G. The orphan receptor cDNA RDC7 encodes an A1 adenosine receptor, EMBO J., 1991, 10, 1677-1682. Furlong, T. J.; Pierce, K. D.; Selbie, L. A.; Shine. J. Molecular characterization of a human brain adenosine A2 receptor. Brain Res. Mol. Brain Res., 1992, 15, 62-66. Mahan, L. C.; McVittie, L. D.; Smyk-Randall, E. M.; Nakata, H.; Monsma, F. J. Jr.; Gerfen, C. R.; Sibley, D. R. Cloning and expres-


[124]

[125]

[126]

[127] [128]

[129]

[130]

[131] [132] [133]

[134]

[135]

[136]

[137]

[138] [139]

[140] [141]

[142]

[143]

sion of an A1 adenosine receptor from rat brain. Mol. Pharmacol., 1991, 40, 1-7. Stehle, J. H.; Rivkees, S. A.; Lee, J. J.; Weaver, D. R.; Deeds, J. D.; Reppert, S. M. Molecular cloning and expression of the cDNA for a novel A2-adenosine receptor subtype. Mol. Endocrinol., 1992, 6, 384-393. Zhou, Q. Y.; Li, C.; Olah, M. E.; Johnson, R. A.; Stiles, G. L.; Civelli, O. Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc. Natl. Acad. Sci. USA, 1992, 89, 7432-7436. Fredholm, B. B.; Arslan, G.; Halldner, L.; Kull, B.; Schulte, G.; Wasserman, W. Structure and function of adenosine receptors and their genes, Naunyn Schmiedebergs Arch. Pharmacol., 2000, 362, 364-374. Klotz, K. N.; Quitterer, U.; Englert, M. Effector coupling of human A3 adenosine receptors, Drug Dev. Res., 2000, 50, 80. Baker, S. P.; Scammells, P. J.; Belardinelli, L. Differential A 1adenosine receptor reserve for inhibition of cyclic AMP accumulation and G-protein activation in DDT(1) MF-2 cells. Br. J. Pharmacol., 2000, 130, 1156-1164. Schulte, G.; Fredholm, B. B. Human adenosine A1, A2A, A2B, and A3 receptors expressed in Chinese hamster ovary cells all mediate the phosphorylation of extracellular-regulated kinase 1/2. Mol. Pharmacol., 2000, 58, 477-482. Schulte, G.; Fredholm, B. B. The Gs-coupled adenosine A2B receptor recruits divergent pathways to regulate ERK1/2 and p38. Exp. Cell. Res., 2003, 290, 168-176. Mirabet, M.; Mallol, J.; Lluis, C.; Franco, R. Calcium mobilization in Jurkat cells via A2b adenosine receptors. Br. J. Pharmacol., 1997, 122, 1075-1082. Kenakin, T. Pharmacologic analysis of drug-receptor interaction. Raven Press, New York. 1993. Kenakin, T. Agonist-receptor efficacy. I: Mechanisms of efficacy and receptor promiscuity. Trends Pharmacol. Sci., 1995, 16, 188192. Fredholm, B. B.; Irenius, E.; Kull, B.; Schulte, G. Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem. Pharmacol., 2001, 61, 443-448. Svenningsson, P.; Nomikos, G. G.; Fredholm, B. B. The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. J. Neurosci., 1999, 19, 4011-4022. Fastbom, J.; Fredholm, B. B. Effects of long-term theophylline treatment on adenosine A1-receptors in rat brain: autoradiographic evidence for increased receptor number and altered coupling to Gproteins. Brain Res., 1990, 507, 195-199. Reppert, S. M.; Weaver, D. R.; Stehle, J. H.; Rivkees, S. A. Molecular cloning and characterization of a rat A1-adenosine receptor that is widely expressed in brain and spinal cord. Mol. Endocrinol, 1991, 5, 1037-1048. Svenningsson, P.; Hall, H.; Sedvall, G.; Fredholm, B. B. Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study, Synapse, 1997, 27, 322-335. Johansson, B.; Ahlberg, S.; van der Ploeg, I.; Brene, S.; Lindefors, N.; Persson, H.; Fredholm, B. B. Effect of long term caffeine treatment on A1 and A2 adenosine receptor binding and on mRNA levels in rat brain, Naunyn Schmiedebergs Arch. Pharmacol., 1993, 347, 407-414. Aden, U.; Herlenius, E.; Tang, L. Q.; Fredholm, B. B. Maternal caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain, Pediatr Res., 2000, 48, 177-183. Svenningsson, P.; Le Moine, C.; Kull, B.; Sunahara, R.; Bloch, B.; Fredholm, B. B. Cellular expression of adenosine A2A receptor messenger RNA in the rat central nervous system with special reference to dopamine innervated areas. Neuroscience, 1997, 80, 1171-1185. Rosin, D. L.; Robeva, A.; Woodard, R. L.; Guyenet, P. G.; Linden. J. Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J. Comp Neurol., 1998, 401, 163186. Svenningsson, P.; Le Moine, C.; Fisone, G.; Fredholm, B. B. Distribution. Biochemistry and function of striatal adenosine A2A receptors. Prog. Neurobiol., 1999, 59, 355-396.


[145]

[146]

[147] [148]

[149]

[150]

[151]

[152]

[153]

[154]

[155]

[156]

[157]

[158]

[159]

[160]

[161]

[162]

997

Linden. J. Molecular approach to adenosine receptors: receptormediated mechanisms of tissue protection. Annu. Rev. Pharmacol. Toxicol., 2001, 41, 775-787. Fink, J. S.; Weaver, D. R.; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res. Mol. Brain Res., 1992, 14, 186-195. Schiffmann, S. N.; Libert, F.; Vassart, G.; Vanderhaeghen, J. J. Distribution of adenosine A2 receptor mRNA in the human brain. Neurosci. Lett., 1991, 130, 177-181. Dixon, A. K.; Gubitz, A. K.; Sirinathsinghji, D. J.; Richardson, P. J.; Freeman, T. C. Tissue distribution of adenosine receptor mRNAs in the rat. Br. J. Pharmacol., 1996, 118, 1461-1468. Augood, S. J.; Emson, P. C. Adenosine A2a receptor mRNA is expressed by enkephalin cells but not by somatostatin cells in rat striatum: a co-expression study. Brain Res. Mol. Brain Res., 1994, 22, 204-210. Richardson, P. J.; Dixon, A. K.; Lee, K.; Bell, M. I.; Cox, P. J.; Williams, R.; Pinnock, R. D.; Freeman, T. C. Correlating physiology with gene expression in striatal cholinergic neurones. J. Neurochem., 2000, 74, 839-846. Jarvis, M. F.; Williams, M. Differences in adenosine A-1 and A-2 receptor density revealed by autoradiography in methylxanthinesensitive and insensitive mice. Pharmacol. Biochem. Behav., 1988, 30, 707-714. Parkinson, F. E.; Fredholm, B. B. Autoradiographic evidence for G-protein coupled A2-receptors in rat neostriatum using [3H]-CGS 21680 as a ligand, Naunyn Schmiedebergs Arch. Pharmacol., 1990, 342, 85-89. Hettinger, B. D.; Lee, A.; Linden, J.; Rosin, D. L. Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum. J. Comp Neurol., 2001, 431, 331-346. d'Alcantara, P.; Ledent, C.; Swillens, S.; Schiffmann, S. N. Inactivation of adenosine A2A receptor impairs long term potentiation in the accumbens nucleus without altering basal synaptic transmission. Neuroscience, 2001, 107, 455-464. Martinez-Mir, M. I.; Probst, A.; Palacios, J. M. Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease. Neuroscience, 1991, 42, 697-706. Stone-Elander, S.; Thorell, J. O.; Eriksson, L.; Fredholm, B. B.; Ingvar, M. In vivo biodistribution of [N-11C-methyl]KF 17837 using 3-D-PET: evaluation as a ligand for the study of adenosine A2A receptors, Nucl. Med. Biol., 1997, 24, 187-191. Hirani, E.; Gillies, J.; Karasawa, A.; Shimada, J.; Kase, H.; Opacka-Juffry, J.; Osman, S.; Luthra, S. K.; Hume, S. P.; Brooks, D. J. Evaluation of [4-O-methyl-(11)C]KW-6002 as a potential PET ligand for mapping central adenosine A2A receptors in rats, Synapse, 2001, 42, 164-176. Ishiwata, K.; Noguchi, J.; Wakabayashi, S.; Shimada, J.; Ogi, N.; Nariai, T.; Tanaka, A.; Endo, K.; Suzuki, F.; Senda, M. 11Clabeled KF18446: a potential central nervous system adenosine A2a receptor ligand. J. Nucl. Med., 2000, 41, 345-354. Moresco, R. M.; Todde, S.; Belloli, S.; Simonelli, P.; Panzacchi, A.; Rigamonti, M.; Galli-Kienle, M.; Fazio, F. In vivo imaging of adenosine A2A receptors in rat and primate brain using [11C]SCH442416. Eur. J. Nucl. Med. Mol. Imaging, 2005, 32, 405413. Linden, J.; Taylor, H. E.; Robeva, A. S.; Tucker, A. L.; Stehle, J. H.; Rivkees, S. A.; Fink, J. S.; Reppert, S. M. Molecular cloning and functional expression of a sheep A3 adenosine receptor with widespread tissue distribution. Mol. Pharmacol., 1993, 44, 524532. Salvatore, C. A.; Jacobson, M. A.; Taylor, H. E.; Linden, J.; Johnson, R. G. Molecular cloning and characterization of the human A3 adenosine receptor. Proc. Natl. Acad. Sci. USA, 1993, 90, 1036510369. Fuxe, K.; Ungerstedt, U. Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment with DOPA and dopamine receptor agonists, Med. Biol., 1974, 52, 48-54. Fredholm, B. B.; Fuxe, K.; Agnati, L. Effect of some phosphodiesterase inhibitors on central dopamine mechanisms. Eur. J. Pharmacol., 1976, 38, 31-38.


[164]

[165] [166]

[167] [168]

[169]

[170]

[171]

[172]

[173]

[174]

[175]

[176]

[177]

[178]

[179]

[180]

[181]

Fredholm, B. B. Activation of adenylate cyclase from rat striatum and tuberculum olfactorium by adenosine. Med. Biol., 1977, 55, 262-267. Premont, J.; Perez, M.; Bockaert. J. Adenosine-sensitive adenylate cyclase in rat striatal homogenates and its relationship to dopamine- and Ca2+-sensitive adenylate cyclases. Mol. Pharmacol., 1977, 13, 662-670. Bruns, R. F.; Lu, G. H.; Pugsley, T. A. Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol. Pharmacol., 1986, 29, 331-346. Lee, K. S.; Reddington, M. Autoradiographic evidence for multiple CNS binding sites for adenosine derivatives. Neuroscience, 1986, 19, 535-549. Reddington, M.; Erfurth, A.; Lee, K. S. Heterogeneity of binding sites for N-ethylcarboxamido[3H]adenosine in rat brain: effects of N-ethylmaleimide. Brain Res., 1986, 399, 232-239. Bruns, R. F.; Davis, R. E.; Ninteman, F. W.; Poschel, B. P. H.; Wiley, J. N.; Heffner, T. G. In: Adenosine Antagonists as Pharmacological Tools. Adenosine and adenine nucleotides. Physiology and Pharmacology Eds. Paton, D. M. Taylor & Francis, Basingstoke. 1988, Bridges, A. J.; Bruns, R. F.; Ortwine, D. F.; Priebe, S. R.; Szotek, D. L.; Trivedi, B. K. N6-[2-(3,5-dimethoxyphenyl)-2-(2methylphenyl)ethyl]adenosine and its uronamide derivatives. Novel adenosine agonists with both high affinity and high selectivity for the adenosine A2 receptor. J. Med. Chem., 1988, 31, 1282-1285. Jarvis, M. F.; Jackson, R. H.; Williams, M. Autoradiographic characterization of high-affinity adenosine A2 receptors in the rat brain. Brain Res., 1989, 484, 111-118. Jarvis, M. F.; Schulz, R.; Hutchison, A. J.; Do, U. H.; Sills, M. A.; Williams, M. [3H]CGS 21680, a selective A2 adenosine receptor agonist directly labels A2 receptors in rat brain. J. Pharmacol. Exp. Ther., 1989, 251, 888-893. Brown, S. J.; Gill, R.; Evenden, J. L.; Iversen, S. D.; Richardson, P. J. Striatal A2 receptor regulates apomorphine-induced turning in rats with unilateral dopamine denervation. Psychopharmacology, (Berl) 1991, 103, 78-82. Fredholm, B. B.; Herrera-Marschitz, M.; Jonzon, B.; Lindstrom, K.; Ungerstedt, U. On the mechanism by which methylxanthines enhance apomorphine-induced rotation Behav.iour in the rat. Pharmacol. Biochem. Behav., 1983, 19, 535-541. Heffner, T. G.; Wiley, J. N.; Williams, A. E.; Bruns, R. F.; Coughenour, L. L.; Downs, D. A. Comparison of the Behavioral effects of adenosine agonists and dopamine antagonists in mice. Psychopharmacology, (Berl) 1989, 98, 31-37. Jiang, H.; Jackson-Lewis, V.; Muthane, U.; Dollison, A.; Ferreira, M.; Espinosa, A.; Parsons, B.; Przedborski, S. Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational Behavior in 6-hydroxydopamine-lesioned rats. Brain Res., 1993, 613, 347-351. Popoli, P.; Pezzola, A.; de Carolis, A. S. Modulation of striatal adenosine A1 and A2 receptors induces rotational Behav.iour in response to dopaminergic stimulation in intact rats. Eur. J. Pharmacol., 1994, 257, 21-25. Ferre, S.; von Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci. USA, 1991, 88, 7238-7241. Hillion, J.; Canals, M.; Torvinen, M.; Casado, V.; Scott, R.; Terasmaa, A.; Hansson, A.; Watson, S.; Olah, M. E.; Mallol, J.; Canela, E. I.; Zoli, M.; Agnati, L. F.; Ibanez, C. F.; Lluis, C.; Franco, R.; Ferre, S.; Fuxe, K. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J. Biol. Chem., 2002, 277, 18091-18097. Schiffmann, S. N.; Jacobs, O.; Vanderhaeghen, J. J. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J. Neurochem., 1991, 57, 1062-1067. Johansson, B.; Georgiev, V.; Fredholm, B. B. Distribution and postnatal ontogeny of adenosine A2A receptors in rat brain: comparison with dopamine receptors. Neuroscience, 1997, 80, 11871207. Pollack, A. E.; Harrison, M. B.; Wooten, G. F.; Fink, J. S. Differential localization of A2a adenosine receptor mRNA with D1 and D2 dopamine receptor mRNA in striatal output pathways following a

Burnstock et al.

[182]

[183]

[184] [185]

[186]

[187]

[188] [189]

[190]

[191]

[192]

[193]

[194] [195]

[196]

[197] [198]

[199]

selective lesion of striatonigral neurons. Brain Res., 1993, 631, 161-166. Svenningsson, P.; Nomikos, G. G.; Fredholm, B. B. Biphasic changes in locomotor Behavior and in expression of mRNA for NGFI-A and NGFI-B in rat striatum following acute caffeine administration. J. Neurosci., 1995, 15, 7612-7624. Svenningsson, P.; Nomikos, G. G.; Ongini, E.; Fredholm, B. B. Antagonism of adenosine A2A receptors underlies the Behav.ioural activating effect of caffeine and is associated with reduced expression of messenger RNA for NGFI-A and NGFI-B in caudateputamen and nucleus accumbens. Neuroscience, 1997, 79, 753-764. Boegman, R. J.; Vincent, S. R. Involvement of adenosine and glutamate receptors in the induction of c-fos in the striatum by haloperidol. Synapse, 1996, 22, 70-77. Chen, J. F.; Moratalla, R.; Impagnatiello, F.; Grandy, D. K.; Cuellar, B.; Rubinstein, M.; Beilstein, M. A.; Hackett, E.; Fink, J. S.; Low, M. J.; Ongini, E.; Schwarzschild, M. A. The role of the D 2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)mediated Behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice. Proc. Natl. Acad. Sci. USA, 2001, 98, 1970-1975. Pinna, A.; Wardas, J.; Cozzolino, A.; Morelli, M. Involvement of adenosine A2A receptors in the induction of c-fos expression by clozapine and haloperidol. Neuropsychopharmacology, 1999, 20, 44-51. Svenningsson, P.; Fourreau, L.; Bloch, B.; Fredholm, B. B.; Gonon, F.; Le Moine, C. Opposite tonic modulation of dopamine and adenosine on c-fos gene expression in striatopallidal neurons. Neuroscience, 1999, 89, 827-837. Greengard, P. The neurobiology of slow synaptic transmission. Science, 2001, 294, 1024-1030. Svenningsson, P.; Lindskog, M.; Rognoni, F.; Fredholm, B. B.; Greengard, P.; Fisone, G. Activation of adenosine A2A and dopamine D1 receptors stimulates cyclic AMP-dependent phosphorylation of DARPP-32 in distinct populations of striatal projection neurons. Neuroscience, 1998, 84, 223-228. Lindskog, M.; Svenningsson, P.; Fredholm, B. B.; Greengard, P.; Fisone, G. Activation of dopamine D2 receptors decreases DARPP32 phosphorylation in striatonigral and striatopallidal projection neurons via different mechanisms. Neuroscience, 1999, 88, 10051008. Svenningsson, P.; Lindskog, M.; Ledent, C.; Parmentier, M.; Greengard, P.; Fredholm, B. B.; Fisone, G. Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors. Proc. Natl. Acad. Sci. USA, 2000, 97, 1856-1860. Lindskog, M.; Svenningsson, P.; Pozzi, L.; Kim, Y.; Fienberg, A. A.; Bibb, J. A.; Fredholm, B. B.; Nairn, A. C.; Greengard, P.; Fisone, G. Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Nature, 2002, 418, 774-778. Chen. J. F.; Xu, K.; Petzer, J. P.; Staal, R.; Xu, Y. H.; Beilstein, M.; Sonsalla, P. K.; Castagnoli, K.; Castagnoli, N. Jr.; Schwarzschild, M. A. Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci., 2001, 21, RC143. Blandini, F. Adenosine receptors and L-DOPA-induced dyskinesia in Parkinson's disease: potential targets for a new therapeutic approach. Exp. Neurol., 2003, 184, 556-560. Fredholm, B. B.; Battig, K.; Holmen, J.; Nehlig, A.; Zvartau, E. E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev., 1999, 51, 83-133. Yaar, R.; Jones, M. R.; Chen. J. F.; Ravid, K. Animal models for the study of adenosine receptor function. J. Cell. Physiol., 2005, 202, 9-20. Halldner, L.; Lozza, G.; Lindstrom, K.; Fredholm, B. B. Lack of tolerance to motor stimulant effects of a selective adenosine A2A receptor antagonist. Eur. J. Pharmacol., 2000, 406, 345-354. Haslam, R. J.; Cusack, N. J. Blood platelet receptors for ADP and for adenosine. In: Purinergic receptors Eds. Burnstock, G. Chapman and Hall, London. 1981, PP: 221-285. Sollevi, A.; Torssell, L.; Fredholm, B. B.; Settergren, G.; Blomback, M. Adenosine spaRes. platelets during cardiopulmonary bypass in man without causing systemic vasodilatation, Scand J. Thorac. Cardiovasc. Surg., 1985, 19, 155-159.


[201]

[202] [203]

[204] [205]

[206] [207]

[208]

[209]

[210]

[211] [212]

[213]

[214]

[215]

[216] [217]

[218]

[219] [220]

Gessi, S.; Varani, K.; Merighi, S.; Ongini, E.; Borea, P. A. A(2A) adenosine receptors in human peripheral blood cells. Br. J. Pharmacol., 2000, 129, 2-11. Ledent, C.; Vaugeois, J. M.; Schiffmann, S. N.; Pedrazzini, T.; El Yacoubi, M.; Vanderhaeghen, J. J.; Costentin, J.; Heath, J. K.; Vassart, G.; Parmentier, M. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature, 1997, 388, 674-678. Cronstein, B. N. Adenosine, an endogenous anti-inflammatory agent. J. Appl. Physiol., 1994, 76, 5-13. Haskó, G.; Pacher, P. A 2A receptors in inflammation and injury: lessons learned from transgenic animals. J. Leukoc. Biol., 2008, 83, 447-455. Ohta, A.; Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature, 2001, 414, 916-920. Okusa, M. D.; Linden, J.; Macdonald, T.; Huang, L. Selective A2A adenosine receptor activation reduces ischemia-reperfusion injury in rat kidney, Am J. Physiol., 1999, 277, F404-412. Jenner, P.; Mori, A.; Hauser, R.; Morelli, M.; Fredholm, B. B.; Chen, J. F. Adenosine, adenosine A 2A antagonists, and Parkinson's disease, Parkinsonism Relat. Disord., 2009, 15, 406-413. Ciccarelli, R.; Ballerini, P.; Sabatino, G.; Rathbone, M. P.; D'Onofrio, M.; Caciagli, F.; Di Iorio, P. Involvement of astrocytes in purine-mediated reparative processes in the brain. Int. J. Dev. Neurosci., 2001, 19, 395-414. Shin, C. Y.; Jang, E. S.; Choi, J. W.; Ryu, J. R.; Kim, W. K.; Kim, H. C.; Choi, C. R.; Ko, K. H. Adenosine and purine nucleosides protect rat primary astrocytes from peroxynitrite-potentiated, glucose deprivation-induced death: preservation of intracellular ATP level. Exp. Neurol., 2002, 176, 175-182. Bourke, R. S.; Kimelberg, H. K.; Daze, M.; Church, G. Swelling and ion uptake in cat cerebrocortical slices: control by neurotransmitters and ion transport mechanisms. Neurochem. Res., 1983, 8, 524. Bourke, R. S.; Kimelberg, H. K.; Daze, M. A. Effects of inhibitors and adenosine on (HCO3- /CO2)-stimulated swelling and Cl- uptake in brain slices and cultured astrocytes. Brain Res., 1978, 154, 196202. Kimelberg, H. K. Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia, 2005, 50, 389397. Hindley, S.; Herman, M. A.; Rathbone, M. P. Stimulation of reactive astrogliosis in vivo by extracellular adenosine diphosphate or an adenosine A2 receptor agonist. J. Neurosci. Res., 1994, 38, 399406. Abbracchio, M. P.; Ceruti, S.; Brambilla, R.; Barberi, D.; Camurri, A.; Francheschi, C.; Giammarioli, A. M.; Jacobson, K. A.; Cattabeni, F.; Malorni, W. Adenosine A3 receptors and viability in astrocytes, Drug Dev. Res., 1998, 45, 379-386. Ciccarelli, R.; Di Iorio, P.; Ballerini, P.; Ambrosini, G.; Giuliani, P.; Tiboni, G. M.; Caciagli, F. Effects of exogenous ATP and related analogues on the proliferation rate of dissociated primary cultuRes. of rat astrocytes. J. Neurosci. Res., 1994, 39, 556-566. Nishizaki, T.; Nagai, K.; Nomura, T.; Tada, H.; Kanno, T.; Tozaki, H.; Li, X. X.; Kondoh, T.; Kodama, N.; Takahashi, E.; Sakai, N.; Tanaka, K.; Saito, N. A new neuromodulatory pathway with a glial contribution mediated via A2a adenosine receptors. Glia, 2002, 39, 133-147. Li, X. X.; Nomura, T.; Aihara, H.; Nishizaki, T. Adenosine enhances glial glutamate efflux via A2a adenosine receptors. Life Sci., 2001, 68, 1343-1350. Fredholm, B. B.; Chen, J. F.; Cunha, R. A.; Svenningsson, P.; Vaugeois, J.-M. () Adenosine and brain function. In: International Review of Neurobiology Eds. Harris. R. A.; Janner. P.; Bradley R. J. Elsevier, London. 2005, PP: 191-270 Magistretti, P. J.; Hof, P. R.; Martin, J. L. Adenosine stimulates glycogenolysis in mouse cerebral cortex: a possible coupling mechanism between neuronal activity and energy metabolism. J. Neurosci., 1986, 6, 2558-2562. Tsacopoulos, M.; Magistretti, P. J. Metabolic coupling between glia and neurons. J. Neurosci., 1996, 16, 877-885. Schwaninger, M.; Petersen, N.; Prinz, S.; Sallmann, S.; Neher, M.; Spranger, M. Adenosine-induced expression of interleukin-6 in astrocytes through protein kinase A and NF-IL-6. Glia, 2000, 31, 5158.


[222] [223]

[224]

[225] [226]

[227] [228] [229] [230] [231]

[232]

[233]

[234]

[235]

[236]

[237] [238] [239]

[240]

[241] [242]

[243]

999

Fredholm, B. B.; Altiok, N. Adenosine A2B receptor signalling is altered by stimulation of bradykinin or interleukin receptors in astroglioma cells. Neurochem. Int., 1994, 25, 99-102. Back, S. A.; Rivkees, S. A. Emerging concepts in periventricular white matter injury. Semin. Perinatol., 2004, 28, 405-414. Turner, C. P.; Seli, M.; Ment, L.; Stewart, W.; Yan, H.; Johansson, B.; Fredholm, B. B.; Blackburn, M.; Rivkees, S. A. A1 adenosine receptors mediate hypoxia-induced ventriculomegaly. Proc. Natl. Acad. Sci. USA, 2003, 100, 11718-11722. Gebicke-Haerter, P. J.; Christoffel, F.; Timmer, J.; Northoff, H.; Berger, M.; Van Calker, D. Both adenosine A1- and A2-receptors are required to stimulate microglial proliferation. Neurochem. Int., 1996, 29, 37-42. Hammarberg, C.; Schulte, G.; Fredholm, B. B. Evidence for functional adenosine A3 receptors in microglia cells. J. Neurochem., 2003, 86, 1051-1054. Balcar, V. J.; Li, Y.; Killinger, S.; Bennett, M. R. Autoradiography of P2x ATP receptors in the rat brain. Br. J. Pharmacol., 1995, 115, 302-306. Norenberg, W.; Illes, P. Neuronal P2X receptors: localisation and functional properties, Naunyn Schmiedebergs Arch. Pharmacol. , 2000, 362, 324-339. North, R. A. Molecular physiology of P2X receptors. Physiol. Rev., 2002, 82, 1013-1067. Egan, T. M.; Khakh, B. S. Contribution of calcium ions to P2X channel responses. J. Neurosci., 2004, 24, 3413-3420. Egan, T. M.; Samways, D. S.; Li, Z. Biophysics of P2X receptors, Pflugers Arch., 2006, 452, 501-512. Edwards, F. A.; Robertson, S. J.; Gibb, A. J. Properties of ATP receptor-mediated synaptic transmission in the rat medial habenula. Neuropharmacology, 1997, 36, 1253-1268. Garcia-Guzman, M.; Soto, F.; Gomez-Hernandez, J. M.; Lund, P. E.; Stuhmer, W. Characterization of recombinant human P2X4 receptor reveals Pharmacological differences to the rat homologue. Mol. Pharmacol., 1997, 51, 109-118. Rogers, M.; Colquhoun, L. M.; Patrick, J. W.; Dani, J. A. Calcium flux through predominantly independent purinergic ATP and nicotinic acetylcholine receptors. J. NeuroPhysiol., 1997, 77, 14071417. Garaschuk, O.; Schneggenburger, R.; Schirra, C.; Tempia, F.; Konnerth, A. Fractional Ca2+ currents through somatic and dendritic glutamate receptor channels of rat hippocampal CA1 pyramidal neurones. J. Physiol. London, 1996, 491, 757-772. Fucile, S.; Palma, E.; Mileo, A. M.; Miledi, R.; Eusebi, F. Human neuronal threonine-for-leucine-248 7 mutant nicotinic acetylcholine receptors are highly Ca2+ permeable. Proc. Natl. Acad. Sci. USA, 2000, 97, 3643-3648. Ragozzino, D.; Barabino, B.; Fucile, S.; Eusebi, F. Ca2+ permeability of mouse and chick nicotinic acetylcholine receptors expressed in transiently transfected human cells. J. Physiol. London, 1998, 507, 749-757. Spruston, N.; Jonas, P.; Sakmann, B. Dendritic glutamate receptor channels in rat hippocampal CA3 and CA1 pyramidal neurons. J. Physiol. London, 1995, 482, 325-352. Mori, H.; Mishina, M. Structure and function of the NMDA receptor channel. Neuropharmacology, 1995, 34, 1219-1237. Nowak, L.; Bregestovski, P.; Ascher, P.; Herbet, A.; Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature, 1984, 307, 462-465. Kirischuk, S.; Matiash, V.; Kulik, A.; Voitenko, N.; Kostyuk, P.; Verkhratsky, A. Activation of P2-purino-, a1-adreno and H1histamine receptors triggers cytoplasmic calcium signalling in cerebellar Purkinje neurons. Neuroscience, 1996, 73, 643-647. Lalo, U.; Voitenko, N.; Kostyuk, P. Iono- and metabotropically induced purinergic calcium signalling in rat neocortical neurons. Brain Res., 1998, 799, 285-291. Sawada, K.; Echigo, N.; Juge, N.; Miyaji, T.; Otsuka, M.; Omote, H.; Yamamoto, A.; Moriyama, Y. Identification of a vesicular nucleotide transporter. Proc. Natl. Acad. Sci. USA, 2008, 105, 56835686. Robertson, S. J.; Edwards, F. A. ATP and glutamate are released from separate neurones in the rat medial habenula nucleus: frequency dependence and adenosine-mediated inhibition of release. J. Physiol., 1998, 508, 691-701.


[245] [246]

[247] [248] [249]

[250] [251]

[252]

[253] [254]

[255]

[256]

[257] [258] [259]

[260] [261] [262]

[263]

[264]

[265]

[266] [267]

Wieraszko, A.; Seyfried, T. N. Involvement of ATP as a neurotransmitter in the hippocampus Ann. NY Acad. Sci., 1990, 603, 494496. Evans, R. J.; Derkach, V.; Surprenant, A. ATP mediates fast synaptic transmission in mammalian neurons. Nature, 1992, 357, 503505. Bliss, T. V.; Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 1993, 361, 3139. Bliss, T. V.; Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol., 1973, 232, 331-356. Malenka, R. C.; Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron, 2004, 44, 5-21. Fujii, S. ATP- and adenosine-mediated signaling in the central nervous system: the role of extracellular ATP in hippocampal longterm potentiation. J. Pharmacol. Sci., 2004, 94, 103-106. Ikeda, H.; Tsuda, M.; Inoue, K.; Murase, K. Long-term potentiation of neuronal excitation by neuron-glia interactions in the rat spinal dorsal horn. Eur. J. Neurosci., 2007, 25, 1297-1306. Yamazaki, Y.; Kaneko, K.; Fujii, S.; Kato, H.; Ito, K. Long-term potentiation and long-term depression induced by local application of ATP to hippocampal CA1 neurons of the guinea pig, Hippocampus, 2003, 13, 81-92. Zhang, Y.; Deng, P.; Li, Y.; Xu, Z. C. Enhancement of excitatory synaptic transmission in spiny neurons after transient forebrain ischemia. J. NeuroPhysiol., 2006, 95, 1537-1544. Pankratov, Y. V.; Lalo, U. V.; Krishtal, O. A. Role for P2X receptors in long-term potentiation. J. Neurosci., 2002, 22, 8363-8369. Wang, Y.; Mackes, J.; Chan, S.; Haughey, N. J.; Guo, Z.; Ouyang, X.; Furukawa, K.; Ingram, D. K.; Mattson, M. P. Impaired longterm depression in P2X3 deficient mice is not associated with a spatial learning deficit. J. Neurochem., 2006, 99, 1425-1434. Lalo, U.; Verkhratsky, A.; Pankratov, Y. Ivermectin potentiates ATP-induced ion currents in cortical neurones: evidence for functional expression of P2X4 receptors? Neurosci. Lett., 2007, 421, 158-162. Sim, J. A.; Chaumont, S.; Jo, J.; Ulmann, L.; Young, M. T.; Cho, K.; Buell, G.; North, R. A.; Rassendren, F. Altered hippocampal synaptic potentiation in P2X4 knock-out mice. J. Neurosci., 2006, 26, 9006-9009. Anderson, C. M.; Nedergaard, M. Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons. Trends Neurosci., 2006, 29, 257-262. Surprenant, A.; North, R. A. Signaling at purinergic P2X receptors, Annu. Rev. Physiol., 2009, 71, 333-359. Collo, G.; Neidhart, S.; Kawashima, E.; Kosco-Vilbois, M.; North, R. A.; Buell, G. Tissue distribution of the P2X7 receptor. Neuropharmacology, 1997, 36, 1277-1283. Sperlagh, B.; Vizi, E. S.; Wirkner, K.; Illes, P. P2X7 receptors in the nervous system, Prog. Neurobiol., 2006, 78, 327-346. Sim, J. A.; Young, M. T.; Sung, H. Y.; North, R. A.; Surprenant, A. Reanalysis of P2X7 receptor expression in rodent brain. J. Neurosci., 2004, 24, 6307-6314. Miras-Portugal, M. T.; Diaz-Hernandez, M.; Giraldez, L.; Hervas, C.; Gomez-Villafuertes, R.; Sen, R. P.; Gualix, J.; Pintor. J. P2X7 receptors in rat brain: presence in synaptic terminals and granule cells. Neurochem. Res., 2003, 28, 1597-1605. Deuchars, S. A.; Atkinson, L.; Brooke, R. E.; Musa, H.; Milligan, C. J.; Batten, T. F.; Buckley, N. J.; Parson, S. H.; Deuchars. J. Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J. Neurosci., 2001, 21, 7143-7152. Ireland, M. F.; Noakes, P. G.; Bellingham, M. C. P2X7-like receptor subunits enhance excitatory synaptic transmission at central synapses by presynaptic mechanisms. Neuroscience, 2004, 128, 269-280. Kukley, M.; Stausberg, P.; Adelmann, G.; Chessell, I. P.; Dietrich, D. Ecto-nucleotidases and nucleoside transporters mediate activation of adenosine receptors on hippocampal mossy fibers by P2X7 receptor agonist 2'-3'-O-(4-benzoylbenzoyl)-ATP. J. Neurosci., 2004, 24, 7128-7139. Hussl, S.; Boehm, S. Functions of neuronal P2Y receptors. Pflugers Arch., 2006, 452, 538-551. Erb, L.; Liao, Z.; Seye, C. I.; Weisman, G. A. P2 receptors: intracellular signaling. Pflugers Arch., 2006, 452, 552-562.

Burnstock et al. [268]

[269] [270]

[271]

[272]

[273] [274]

[275]

[276] [277]

[278] [279]

[280]

[281]

[282] [283]

[284]

[285]

[286] [287] [288] [289] [290] [291]

Verkhratsky, A. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol. Rev., 2005, 85, 201-279. Mironov, S. L. Metabotropic ATP receptor in hippocampal and thalamic neurones: Pharmacology and modulation of Ca2+ mobilizing mechanisms. Neuropharmacology, 1994, 33, 1-13. Nishizaki, T.; Mori, M. Diverse signal transduction pathways mediated by endogenous P2 receptors in cultured rat cerebral cortical neurons. J. Neurophysiol., 1998, 79, 2513-2521. Mammano, F.; Frolenkov, G. I.; Lagostena, L.; Belyantseva, I. A.; Kurc, M.; Dodane, V.; Colavita, A.; Kachar, B. ATP-Induced Ca2+ release in cochlear outer hair cells: localization of an inositol triphosphate-gated Ca2+ store to the base of the sensory hair bundle. J. Neurosci., 1999, 19, 6918-6929. Currie, K. P.; Fox, A. P. ATP serves as a negative feedback inhibitor of voltage-gated Ca2+ channel currents in cultured bovine adrenal chromaffin cells. Neuron, 1996, 16, 1027-1036. Diverse-Pierluissi, M.; Dunlap, K.; Westhead, E. W. Multiple actions of extracellular ATP on calcium currents in cultured bovine chromaffin cells. Proc. Natl. Acad. Sci. USA, 1991, 88, 1261-1265. Powell, A. D.; Teschemacher, A. G.; Seward, E. P. P2Y purinoceptors inhibit exocytosis in adrenal chromaffin cells via modulation of voltage-operated calcium channels. J. Neurosci., 2000, 20, 606616. Elmslie, K. S. Calcium current modulation in frog sympathetic neurones: multiple neurotransmitters and G proteins. J. Physiol., 1992, 451, 229-246. Filippov, A. K.; Brown, D. A. Activation of nucleotide receptors inhibits high-threshold calcium currents in NG108-15 neuronal hybrid cells. Eur. J. Neurosci., 1996, 8, 1149-1155. Simon, J.; Filippov, A. K.; Goransson, S.; Wong, Y. H.; Frelin, C.; Michel, A. D.; Brown, D. A.; Barnard, E. A. Characterization and channel coupling of the P2Y12 nucleotide receptor of brain capillary endothelial cells. J. Biol. Chem., 2002, 277, 31390-31400. Adams, P. R.; Brown, D. A.; Constanti, A. Pharmacological inhibition of the M-current. J. Physiol., 1982, 332, 223-262. Lopez, H. S.; Adams, P. R. A G Protein mediates the inhibition of the voltage-dependent potassium M current by muscarine, LHRH, Substance P and UTP in bullfrog sympathetic neurons. Eur. J. Neurosci., 1989, 1, 529-542. Ikeuchi, Y.; Nishizaki, T. ATP-evoked potassium currents in rat striatal neurons are mediated by a P2 purinergic receptor. Neurosci. Lett., 1995, 190, 89-92. Ikeuchi, Y.; Nishizaki, T.; Okada, Y. Repetitive applications of ATP potentiate potassium current by Ca2+/calmodulin kinase in cultured rat hippocampal neurons. Neurosci. Lett., 1996, 203, 115118. Ikeuchi, Y.; Nishizaki, T. P2 purinoceptor-operated potassium channel in rat cerebellar neurons. Biochem. Biophys. Res. Commun., 1996, 218, 67-71. Mendoza-Fernandez, V.; Andrew, R. D.; Barajas-Lopez, C. ATP inhibits glutamate synaptic release by acting at P2Y receptors in pyramidal neurons of hippocampal slices. J. Pharmacol. Exp. Ther., 2000, 293, 172-179. Price, G. D.; Robertson, S. J.; Edwards, F. A. Long-term potentiation of glutamatergic synaptic transmission induced by activation of presynaptic P2Y receptors in the rat medial habenula nucleus. Eur. J. Neurosci., 2003, 17, 844-850. von Kugelgen, I.; Koch, H.; Starke, K. P2-receptor-mediated inhibition of serotonin release in the rat brain cortex. Neuropharmacology, 1997, 36, 1221-1227. von Kugelgen, I.; Spath, L.; Starke, K. Evidence for P2purinoceptor-mediated inhibition of noradrenaline release in rat brain cortex. Br. J. Pharmacol., 1994, 113, 815-822. Butt, A. M.; Hamilton, N.; Hubbard, P.; Pugh, M.; Ibrahim, M. Synantocytes: the fifth element. J. Anat, 2005, 207, 695-706. Kettenmann, H.; Verkhratsky, A. Neuroglia: the 150 years after. Trends Neurosci., 2008, 31, 653-659. Verkhratsky, A. Patching the glia reveals the functional organisation of the brain. Pflugers Arch., 2006, 453, 411-420. Verkhratsky, A.; Butt, A. Glial Neurobiology. A textbook. John Wiley & Sons, Chichester. 2007. Verkhratsky, A. Neuronismo y reticulismo: neuronal-glial circuits unify the reticular and neuronal theories of brain organization. Acta Physiol., (Oxf) 2009, 195, 111-122.

Purinoceptors in the Brain [292] [293]

[294] [295]

[296] [297] [298]

[299] [300] [301] [302] [303] [304]

[305] [306] [307] [308]

[309] [310]

[311]

[312]

[313]

[314]

[315]

[316] [317]

Nedergaard, M.; Dirnagl, U. Role of glial cells in cerebral ischemia. Glia, 2005, 50, 281-286. Tian, G. F.; Azmi, H.; Takano, T.; Xu, Q.; Peng, W.; Lin, J.; Oberheim, N.; Lou, N.; Wang, X.; Zielke, H. R.; Kang, J.; Nedergaard, M. An astrocytic basis of epilepsy. Nat. Med., 2005, 11, 973-981. Giaume, C.; Kirchhoff, F.; Matute, C.; Reichenbach, A.; Verkhratsky, A. Glia: the fulcrum of brain diseases. Cell Death Differ., 2007, 14, 1324-1335. Rodriguez, J. J.; Olabarria, M.; Chvatal, A.; Verkhratsky, A. Astroglia in dementia and Alzheimer's disease. Cell Death Differ., 2009, 16, 378-385. Abbracchio, M. P.; Ceruti, S. Roles of P2 receptors in glial cells: focus on astrocytes. Purinergic Signal., 2006, 2, 595-604. Farber, K.; Kettenmann, H. Purinergic signaling and microglia. Pflugers Arch., 2006, 452, 615-621. Fellin, T.; Sul, J. Y.; D'Ascenzo, M.; Takano, H.; Pascual, O.; Haydon, P. G. Bidirectional astrocyte-neuron communication: the many roles of glutamate and ATP, Novartis Found. Symp., 2006, 276, 208-217; discussion 217-221, 233-207, 275-281. Fields, R. D.; Stevens, B. ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci., 2000, 23, 625-633. Fischer, W.; Krugel, U. P2Y receptors: focus on structural. Pharmacological and functional aspects in the brain. Curr. Med. Chem., 2007, 14, 2429-2455. Inoue, K. Microglial activation by purines and pyrimidines. Glia 2002, 40, 156-163. Inoue, K. Purinergic systems in microglia. Cell. Mol. Life Sci., 2008, 65, 3074-3080. Newman, E. A. Glial Cell. inhibition of neurons by release of ATP. J. Neurosci., 2003, 23, 1659-1666. Newman, E. A. A purinergic dialogue between glia and neurons in the retina, Novartis Found. Symp., 2006, 276, 193-202; discussion 202-197, 233-197, 275-181. Verkhratsky, A.; Steinhauser, C. Ion channels in glial cells. Brain Res. Brain Res. Rev., 2000, 32, 380-412. Anderson, C. M.; Bergher, J. P.; Swanson, R. A. ATP-induced ATP release from astrocytes. J. Neurochem., 2004, 88, 246-256. Evanko, D. S.; Zhang, Q.; Zorec, R.; Haydon, P. G. Defining pathways of loss and secretion of chemical messengers from astrocytes. Glia, 2004, 47, 233-240. Suadicani, S. O.; Brosnan, C. F.; Scemes, E. P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J. Neurosci., 2006, 26, 1378-1385. Dixon, S. J.; Yu, R.; Panupinthu, N.; Wilson, J. X. Activation of P2 nucleotide receptors stimulates acid efflux from astrocytes. Glia, 2004, 47, 367-376. Fumagalli, M.; Brambilla, R.; D'Ambrosi, N.; Volonte, C.; Matteoli, M.; Verderio, C.; Abbracchio, M. P. Nucleotide-mediated calcium signaling in rat cortical astrocytes: Role of P2X and P2Y receptors. Glia, 2003, 43, 218-203. Jabs, R.; GuenTher. E.; Marquordt, K.; Wheeler-Schilling, T. H. Evidence for P2X3, P2X4 , P2X5 but not for P2X7 containing purinergic receptors in Muller cells of the rat retina. Brain Res. Mol. Brain Res., 2000, 76, 205-210. Pannicke, T.; Fischer, W.; Biedermann, B.; Schadlich, H.; Grosche, J.; Faude, F.; Wiedemann, P.; Allgaier, C.; Illes, P.; Burnstock, G.; Reichenbach, A. P2X7 receptors in Muller glial cells from the human retina. J. Neurosci., 2000, 20, 5965-5972. Lalo, U.; Pankratov, Y.; Wichert, S. P.; Rossner, M. J.; North, R. A.; Kirchhoff, F.; Verkhratsky, A. P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J. Neurosci., 2008, 28, 5473-5480. Franke, H.; Grosche, J.; Schadlich, H.; Krugel, U.; Allgaier, C.; Illes, P. P2X receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience, 2001, 108, 421-429. Kanjhan, R.; Housley, G. D.; Thorne, P. R.; Christie, D. L.; Palmer, D. J.; Luo, L.; Ryan, A. F. Localization of ATP-gated ion channels in cerebellum using P2x2R subunit-specific antisera. Neuroreport, 1996, 7, 2665-2669. Kukley, M.; Barden, J. A.; Steinhauser, C.; Jabs, R. Distribution of P2X receptors on astrocytes in juvenile rat hippocampus. Glia, 2001, 36, 11-21. Magoski, N. S.; Walz, W. Ionic dependence of a P2-purinoceptor mediated depolarization of cultured astrocytes. J. Neurosci. Res., 1992, 32, 530-538.


[319]

[320] [321]

[322]

[323]

[324]

[325] [326]

[327]

[328]

[329]

[330]

[331] [332]

[333]

[334] [335]

[336]

[337]

[338]

1001

Walz, W.; Gimpl, G.; Ohlemeyer, C.; Kettenmann, H. Extracellular ATP-induced currents in astrocytes: involvement of a cation channel. J. Neurosci. Res., 1994, 38, 12-18. Jabs, R.; Matthias, K.; Grote, A.; Grauer, M.; Seifert, G.; Steinhauser, C. Lack of P2X receptor mediated currents in astrocytes and GluR type glial cells of the hippocampal CA1 region. Glia, 2007, 55, 1648-1655. Kirischuk, S.; Moller, T.; Voitenko, N.; Kettenmann, H.; Verkhratsky, A. ATP-induced cytoplasmic calcium mobilization in BergmAnn. glial cells. J. Neurosci., 1995, 15, 7861-7871. Hamilton, N.; Vayro, S.; Kirchhoff, F.; Verkhratsky, A.; Robbins, J.; Gorecki, D. C.; Butt, A. M. Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia, 2008, 56, 734-749. Duan, S.; Anderson, C. M.; Keung, E. C.; Chen, Y.; Swanson, R. A. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J. Neurosci., 2003, 23, 1320-1328. Hung, A. C.; Sun, S. H. The P2X7 receptor-mediated phospholipase D activation is regulated by both PKC-dependent and PKCindependent pathways in a rat brain-derived Type-2 astrocyte Cell. line, RBA-2. Cell. Signal., 2002, 14, 83-92. John, G. R.; Simpson, J. E.; Woodroofe, M. N.; Lee, S. C.; Brosnan, C. F. Extracellular nucleotides differentially regulate interleukin-1beta signaling in primary human astrocytes: implications for inflammatory gene expression. J. Neurosci., 2001, 21, 4134-4142. Narcisse, L.; Scemes, E.; Zhao, Y.; Lee, S. C.; Brosnan, C. F. The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes. Glia, 2005, 49, 245-258. Wang, C. M.; Chang, Y. Y.; Sun, S. H. Activation of P2X7 purinoceptor-stimulated TGF-beta 1 mRNA expression involves PKC/MAPK signalling pathway in a rat brain-derived type-2 astrocyte Cell. line, RBA-2. Cell. Signal., 2003, 15, 1129-1137. Panenka, W.; Jijon, H.; Herx, L. M.; Armstrong, J. N.; Feighan, D.; Wei, T.; Yong, V. W.; Ransohoff, R. M.; MacVicar, B. A. P2X7like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase. J. Neurosci., 2001, 21, 7135-7142. Yu, Y.; Ugawa, S.; Ueda, T.; Ishida, Y.; Inoue, K.; Kyaw Nyunt, A.; Umemura, A.; Mase, M.; Yamada, K.; Shimada, S. Cellular localization of P2X7 receptor mRNA in the rat brain. Brain Res., 2008, 1194, 45-55. Ballerini, P.; Rathbone, M. P.; Di Iorio, P.; Renzetti, A.; Giuliani, P.; D'Alimonte, I.; Trubiani, O.; Caciagli, F.; Ciccarelli, R. Rat astroglial P2Z (P2X7) receptors regulate intracellular calcium and purine release. Neuroreport, 1996, 7, 2533-2537. Nobile, M.; Monaldi, I.; Alloisio, S.; Cugnoli, C.; Ferroni, S. ATPinduced, sustained calcium signalling in cultured rat cortical astrocytes: evidence for a non-capacitative, P2X7-like-mediated calcium entry. FEBS Lett., 2003, 538, 71-76. Fellin, T.; Pozzan, T.; Carmignoto, G. Purinergic receptors mediate two distinct glutamate release pathways in hippocampal astrocytes. J. Biol. Chem., 2006, 281, 4274-4284. Franke, H.; Krugel, U.; Grosche, J.; Heine, C.; Hartig, W.; Allgaier, C.; Illes, P. P2Y receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience, 2004, 127, 431-441. Walter, L.; Dinh, T.; Stella, N. ATP induces a rapid and pronounced increase in 2-arachidonoylglycerol production by astrocytes, a response limited by monoacylglycerol lipase. J. Neurosci., 2004, 24, 8068-8074. Kucher, B. M.; Neary, J. T. Bi-functional effects of ATP/P2 receptor activation on tumor necrosis factor-alpha release in lipopolysaccharide-stimulated astrocytes. J. Neurochem., 2005, 92, 525-535. Murakami, K.; Nakamura, Y.; Yoneda, Y. Potentiation by ATP of lipopolysaccharide-stimulated nitric oxide production in cultured astrocytes. Neuroscience, 2003, 117, 37-42. Agresti, C.; Meomartini, M. E.; Amadio, S.; Ambrosini, E.; Volonte, C.; Aloisi, F.; Visentin, S. ATP regulates oligodendrocyte progenitor migration, proliferation, and differentiation: involvement of metabotropic P2 receptors. Brain Res. Brain Res. Rev., 2005, 48, 157-165. Meomartini, M. E.; Amadio, S.; Visentin, S.; Franchini, L.; Aloisi, F.; Volontà, C.; Agresti, C. Expression and functional analysis of P2 receptors in oligodendrocytes. Glia, 2003, 43, (Suppl. 2), 59. Kirischuk, S.; Scherer, J.; Kettenmann, H.; Verkhratsky, A. Activation of P2-purinoreceptors triggered Ca2+ release from InsP3-


[339]

[340] [341] [342]

[343]

[344] [345] [346]

[347] [348] [349]

[350] [351]

[352] [353]

[354]

[355]

[356]

[357]

[358]

[359]

[360]

sensitive internal stoRes. in mammalian oligodendrocytes. J. Physiol., 1995, 483, 41-57. James, G.; Butt, A. M. P2X and P2Y purinoreceptors mediate ATP-evoked calcium signalling in optic nerve glia in situ. Cell. Calcium, 2001, 30, 251-259. Matute, C. P2X7 receptors in oligodendrocytes: a novel target for neuroprotection. Mol. NeuroBiol., 2008, 38, 123-128. Matute, C.; Alberdi, E.; Domercq, M.; Sanchez-Gomez, M. V.; Perez-Samartin, A.; Rodriguez-Antiguedad, A.; Perez-Cerda, F. Excitotoxic damage to white matter. J. Anat, 2007, 210, 693-702. Matute, C.; Torre, I.; Perez-Cerda, F.; Perez-Samartin, A.; Alberdi, E.; Etxebarria, E.; Arranz, A. M.; Ravid, R.; RodriguezAntiguedad, A.; Sanchez-Gomez, M.; Domercq, M. P2X 7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J. Neurosci., 2007, 27, 9525-9533. Hanisch, U. K.; Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci., 2007, 10, 1387-1394. Kettenmann, H.; Ilschner, S. Physiological properties of microGlia Clin. Neuropathol., 1993, 12, 306-307. Ransohoff, R. M.; Perry, V. H. Microglial physiology: unique stimuli, specialized responses, Annu. Rev. Immunol., 2009, 27, 119145. Xiang, Z.; Chen, M.; Ping, J.; Dunn, P.; Lv, J.; Jiao, B.; Burnstock, G. Microglial morphology and its transformation after challenge by extracellular ATP in vitro. J. Neurosci. Res., 2006, 83, 91-101. Moller, T.; Kann, O.; Verkhratsky, A.; Kettenmann, H. Activation of mouse microglial cells affects P2 receptor signaling. Brain Res., 2000, 853, 49-59. Xiang, Z.; Burnstock, G. Expression of P2X receptors on rat microglial cells during early development. Glia, 2005, 52, 119-126. Cavaliere, F.; Dinkel, K.; Reymann, K. Microglia response and P2 receptor participation in oxygen/glucose deprivation-induced cortical damage. Neuroscience, 2005, 136, 615-623. Haas, S.; Brockhaus, J.; Verkhratsky, A.; Kettenmann, H. ATPinduced membrane currents in ameboid microglia acutely isolated from mouse brain slices. Neuroscience, 1996, 75, 257-261. Di Virgilio, F.; Sanz, J. M.; Chiozzi, P.; Falzoni, S. The P2Z/P2X7 receptor of microglial cells: a novel immunomodulatory receptor, Prog. Brain Res., 1999, 120, 355-368. Ferrari, D.; Chiozzi, P.; Falzoni, S.; Dal Susino, M.; Collo, G.; Buell, G.; Di Virgilio, F. ATP-mediated cytotoxicity in microglial cells. NeuroPharmacology, 1997, 36, 1295-1301. Ferrari, D.; Villalba, M.; Chiozzi, P.; Falzoni, S.; RicciardiCastagnoli, P.; Di Virgilio, F. Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J. Immunol., 1996, 156, 1531-1539. Franke, H.; GunTher. A.; Grosche, J.; Schmidt, R.; Rossner, S.; Reinhardt, R.; Faber-Zuschratter, H.; Schneider, D.; Illes, P. P2X7 receptor expression after ischemia in the cerebral cortex of rats. J. Neuropathol Exp. Neurol., 2004, 63, 686-699. Melani, A.; Amadio, S.; Gianfriddo, M.; Vannucchi, M. G.; Volonte, C.; Bernardi, G.; Pedata, F.; Sancesario, G. P2X7 receptor modulation on microglial cells and reduction of brain infarct caused by middle cerebral artery occlusion in rat. J. Cereb. Blood Flow Metab., 2006, 26, 974-982. Sanz, J. M.; Chiozzi, P.; Ferrari, D.; Colaianna, M.; Idzko, M.; Falzoni, S.; Fellin, R.; Trabace, L.; Di Virgilio, F. Activation of microglia by amyloid b requiRes. P2X7 receptor expression. J. Immunol., 2009, 182, 4378-4385. Yiangou, Y.; Facer, P.; Durrenberger, P.; Chessell, I. P.; Naylor, A.; Bountra, C.; Banati, R. R.; Anand, P. COX-2, CB2 and P2X7immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord, BMC Neurol., 2006, 6, 12. Bennett, G. C.; Ford, A. P.; Smith, J. A.; Emmett, C. J.; Webb, T. E.; Boarder, M. R. P2Y receptor regulation of cultured rat cerebral cortical cells: calcium responses and mRNA expression in neurons and glia. Br. J. Pharmacol., 2003, 139, 279-288. Zhu, Y.; Kimelberg, H. K. Cellular expression of P2Y and -AR receptor mRNAs and proteins in freshly isolated astrocytes and tissue sections from the CA1 region of P8-12 rat hippocampus. Brain Res. Dev. Brain Res., 2004, 148, 77-87. Fries, J. E.; Goczalik, I. M.; Wheeler-Schilling, T. H.; Kohler, K.; GuenTher. E.; Wolf, S.; Wiedemann, P.; Bringmann, A.; Reichen-

Burnstock et al.

[361]

[362] [363]

[364]

[365] [366] [367]

[368]

[369]

[370]

[371]

[372] [373]

[374]

[375] [376]

[377] [378]

[379] [380]

[381]

[382]

bach, A.; Francke, M.; Pannicke, T. Identification of P2Y receptor subtypes in human muller glial cells by physiology, single Cell. RT-PCR, and immunohistochemistry. Invest. OphthalMol. Vis. Sci., 2005, 46, 3000-3007. Fries, J. E.; Wheeler-Schilling, T. H.; Kohler, K.; GuenTher. E. Distribution of metabotropic P2Y receptors in the rat retina: a single-Cell. RT-PCR study. Brain Res. Mol. Brain Res., 2004, 130, 16. Verkhratsky, A.; Kettenmann, H. Calcium signalling in glial cells. Trends Neurosci., 1996, 19, 346-352. Verkhratsky, A.; Orkand, R. K.; Kettenmann, H. Glial calcium: homeostasis and signaling function. Physiol. Rev., 1998, 78, 99141. Bernstein, M.; Behnisch, T.; Balschun, D.; Reymann, K. G.; Reiser, G. Pharmacological characterisation of metabotropic glutamatergic and purinergic receptors linked to Ca2+ signalling in hippocampal astrocytes. NeuroPharmacology, 1998, 37, 169-178. Kostyuk, P.; Verkhratsky, A. Calcium stoRes. in neurons and glia. Neuroscience, 1994, 63, 381-404. Bruner, G.; Murphy, S. UTP activates multiple second messenger systems in cultured rat astrocytes. Neurosci. Lett., 1993, 162, 105108. Jimenez, A. I.; Castro, E.; Communi, D.; Boeynaems, J. M.; Delicado, E. G.; Miras-Portugal, M. T. Coexpression of several types of metabotropic nucleotide receptors in single cerebellar astrocytes. J. Neurochem., 2000, 75, 2071-2079. Kastritsis, C. H.; Salm, A. K.; McCarthy, K. Stimulation of the P2Y purinergic receptor on type 1 astroglia results in inositol phosphate formation and calcium mobilization. J. Neurochem., 1992, 58, 1277-1284. Pearce, B.; Langley, D. Purine- and pyrimidine-stimulated phosphoinositide breakdown and intracellular calcium mobilisation in astrocytes. Brain Res., 1994, 660, 329-332. Pearce, B.; Murphy, S.; Jeremy, J.; Morrow, C.; Dandona, P. ATPevoked Ca2+ mobilisation and prostanoid release from astrocytes: P2-purinergic receptors linked to phosphoinositide hydrolysis. J. Neurochem., 1989, 52, 971-977. Centemeri, C.; Bolego, C.; Abbracchio, M. P.; Cattabeni, F.; Puglisi, L.; Burnstock, G.; Nicosia, S. Characterization of the Ca2+ responses evoked by ATP and other nucleotides in mammalian brain astrocytes. Br. J. Pharmacol., 1997, 121, 1700-1706. Piet, R.; Jahr, C. E. Glutamatergic and purinergic receptormediated calcium transients in BergmAnn. glial cells. J. Neurosci., 2007, 27, 4027-4035. Doengi, M.; Deitmer, J. W.; Lohr, C. New evidence for purinergic signaling in the olfactory bulb: A2A and P2Y1 receptors mediate intracellular calcium release in astrocytes. Faseb J., 2008, 22, 23682378. Bennett, M. R.; Buljan, V.; Farnell, L.; Gibson, W. G. Purinergic junctional transmission and propagation of calcium waves in spinal cord astrocyte networks. Biophys J., 2006, 91, 3560-3571. Gallagher, C. J.; Salter, M. W. Differential properties of astrocyte calcium waves mediated by P2Y1 and P2Y2 receptors. J. Neurosci., 2003, 23, 6728-6739. Fam, S. R.; Gallagher, C. J.; Kalia, L. V.; Salter, M. W. Differential frequency dependence of P2Y1- and P2Y2- mediated Ca2+ signaling in astrocytes. J. Neurosci., 2003, 23, 4437-4444. Fam, S. R.; Gallagher, C. J.; Salter, M. W. P2Y1 purinoceptormediated Ca2+ signaling and Ca2+ wave propagation in dorsal spinal cord astrocytes. J. Neurosci., 2000, 20, 2800-2808. Darby, M.; Kuzmiski, J. B.; Panenka, W.; Feighan, D.; MacVicar, B. A. ATP released from astrocytes during swelling activates chloride channels. J. NeuroPhysiol., 2003, 89, 1870-1877. Wang, Z.; Haydon, P. G.; Yeung, E. S. Direct observation of calcium-independent intercellular ATP signaling in astrocytes. Anal. Chem., 2000, 72, 2001-2007. Domercq, M.; Brambilla, L.; Pilati, E.; MArch.aland, J.; Volterra, A.; Bezzi, P. P2Y 1 receptor-evoked glutamate exocytosis from astrocytes: control by tumor necrosis factor- and prostaglandins. J. Biol. Chem., 2006, 281, 30684-30696. Jeremic, A.; Jeftinija, K.; Stevanovic, J.; Glavaski, A.; Jeftinija, S. ATP stimulates calcium-dependent glutamate release from cultured astrocytes. J. Neurochem., 2001, 77, 664-675. Abdipranoto, A.; Liu, G. J.; Werry, E. L.; Bennett, M. R. Mechanisms of secretion of ATP from cortical astrocytes triggered by uridine triphosphate. Neuroreport, 2003, 14, 2177-2181.


[384]

[385] [386]

[387]

[388]

[389]

[390] [391] [392]

[393] [394]

[395]

[396]

[397] [398]

[399]

[400]

[401]

[402]

[403]

Haas, B.; Schipke, C. G.; Peters, O.; Sohl, G.; Willecke, K.; Kettenmann, H. Activity-dependent ATP-waves in the mouse neocortex are independent from astrocytic calcium waves. Cereb. Cortex, 2006, 16, 237-246. Reyes, R. C.; Parpura, V. Mitochondria modulate Ca2+-dependent glutamate release from rat cortical astrocytes. J. Neurosci., 2008, 28, 9682-9691. Reyes, R. C.; Parpura, V. The trinity of Ca2+ sources for the exocytotic glutamate release from astrocytes. Neurochem. Int., 2009, 55, 2-8. Abbracchio, M. P.; Ceruti, S.; Langfelder, R.; Cattabeni, F.; Saffrey, M. J.; Burnstock, G. Effects of ATP analogues and basic fibroblast growth factor on astroglial Cell. differentiation in primary cultuRes. of rat striatum. Int. J. Dev. Neurosci., 1995, 13, 685-693. Bolego, C.; Ceruti, S.; Brambilla, R.; Puglisi, L.; Cattabeni, F.; Burnstock, G.; Abbracchio, M. P. Characterization of the signalling pathways involved in ATP and basic fibroblast growth factorinduced astrogliosis. Br. J. Pharmacol., 1997, 121, 1692-1699. Agresti, C.; Meomartini, M. E.; Amadio, S.; Ambrosini, E.; Serafini, B.; Franchini, L.; Volonte, C.; Aloisi, F.; Visentin, S. Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development. Glia, 2005, 50, 132-144. Bernstein, M.; Lyons, S. A.; Moller, T.; Kettenmann, H. Receptormediated calcium signalling in glial cells from mouse corpus callosum slices. J. Neurosci. Res., 1996, 46, 152-163. Butt, A. M. Neurotransmitter-mediated calcium signalling in oligodendrocyte physiology and pathology. Glia, 2006, 54, 666-675. Light, A. R.; Wu, Y.; Hughen, R. W.; Guthrie, P. B. Purinergic receptors activating rapid intracellular Ca increases in microglia. Neuron Glia Biol., 2006, 2, 125-138. McLarnon, J. G. Purinergic mediated changes in Ca2+ mobilization and functional responses in microglia: effects of low levels of ATP. J. Neurosci. Res., 2005, 81, 349-356. Visentin, S.; Nuccio, C. D.; Bellenchi, G. C. Different patterns of Ca2+ signals are induced by low compared to high concentrations of P2Y agonists in microglia. Purinergic Signal., 2006, 2, 605-617. Wang, X.; Kim, S. U.; van Breemen, C.; McLarnon, J. G. Activation of purinergic P2X receptors inhibits P2Y-mediated Ca2+ influx in human microglia. Cell Calcium, 2000, 27, 205-212. Boucsein, C.; Zacharias, R.; Farber, K.; Pavlovic, S.; Hanisch, U. K.; Kettenmann, H. Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur. J. Neurosci., 2003, 17, 2267-2276. Ogata, T.; Chuai, M.; Morino, T.; Yamamoto, H.; Nakamura, Y.; Schubert, P. Adenosine triphosphate inhibits cytokine release from lipopolysaccharide-activated microglia via P2y receptors. Brain Res., 2003, 981, 174-183. Seo, D. R.; Kim, K. Y.; Lee, Y. B. Interleukin-10 expression in lipopolysaccharide-activated microglia is mediated by extracellular ATP in an autocrine fashion. Neuroreport, 2004, 15, 1157-1161. Seo, D. R.; Kim, S. Y.; Kim, K. Y.; Lee, H. G.; Moon, J. H.; Lee, J. S.; Lee, S. H.; Kim, S. U.; Lee, Y. B. Cross talk between P2 purinergic receptors modulates extracellular ATP-mediated interleukin-10 production in rat microglial cells. Exp. Mol. Med., 2008, 40, 19-26. Koizumi, S.; Shigemoto-Mogami, Y.; Nasu-Tada, K.; Shinozaki, Y.; Ohsawa, K.; Tsuda, M.; Joshi, B. V.; Jacobson, K. A.; Kohsaka, S.; Inoue, K. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature, 2007, 446, 1091-1095. Haynes, S. E.; Hollopeter, G.; Yang, G.; Kurpius, D.; Dailey, M. E.; Gan, W. B.; Julius, D. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci., 2006, 9, 1512-1519. Lecca, D.; Trincavelli, M. L.; Gelosa, P.; Sironi, L.; Ciana, P.; Fumagalli, M.; Villa, G.; Verderio, C.; Grumelli, C.; Guerrini, U.; Tremoli, E.; Rosa, P.; Cuboni, S.; Martini, C.; Buffo, A.; Cimino, M.; Abbracchio, M. P. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair, PLoS ONE, 2008, 3, e3579. Berne, R. M.; Rubio, R.; Curnish, R. R. Release of adenosine from ischemic brain. Effect on cerebral vascular resistance and incorporation into cerebral adenine nucleotides. Circ. Res., 1974, 35, 262271. Boisvert, D. P.; Gregory, P. C.; Harper, A. M. Effect of decreased arterial pCO2 on the pial arteriolar response to adensoine. Adv. Neurol., 1978, 20, 59-63.


[405] [406]

[407] [408]

[409]

[410] [411] [412]

[413] [414] [415]

[416]

[417]

[418] [419]

[420] [421]

[422] [423]

[424]

[425]

[426]

[427]

1003

Gregory, P. C.; Boisvert, D. P.; Harper, A. M. Adenosine response on pial arteries, influence of CO2 and blood pressure. Pflugers Arch., 1980, 386, 187-192. Beck, D. W.; Vinters, H. V.; Moore, S. A.; Hart, M. N.; Henn, F. A.; Cancilla, P. A. Demonstration of adenosine receptors on mouse cerebral smooth muscle membranes. Stroke, 1984, 15, 725-727. Palmer, G. G.; Ghai, G. Adenosine receptors in capillaries and piaarachnoid of rat cerebral cortex. Eur. J. Pharmacol., 1982, 81, 129132. Schutz, W.; Steurer, G.; Tuisl, E. Functional identification of adenylate cyclase-coupled adenosine receptors in rat brain microvessels. Eur. J. Pharmacol., 1982, 85, 177-184. Forrester, T.; Harper, A. M.; MacKenzie, E. T. Effects of intracarotid adenosine triphosphate infusions on cerebral blood flow and metabolism in the anaesthetized baboon. J. Physiol., 1975, 250, 38P-39P. Forrester, T.; Harper, A. M.; MacKenzie, E. T.; Thomson, E. M. Effect of adenosine triphosphate and some derivatives on cerebral blood flow and metabolism. J. Physiol., 1979, 296, 343-355. Alborch, E.; Martin, G. Adenosine and adenine nucleotides: action on the cerebral blood flow and cerebral vascular resistance. Blood Vessels, 1980, 17, 143. Forrester, T. Extracellular nucleotides in exercise: possible effect on brain metabolism. J. Physiol., (Paris), 1978, 74, 477-483. Harper, A. M. In: Effect of ATP and Adenosine on Cerebral Blood Flow and Responses of Pial Arterioles. Adenosine receptors and modulation of Cell. function (eds. V. Stefanovich, K. Rudolphi, P. Schubert),. IRL Press Ltd, Oxford. 1985, PP 395-400 Wu, P. H.; Phillis, J. W. Uptake of adenosine by isolated rat brain capillaries. J. Neurochem., 1982, 38, 687-690. Stefanovich, V. Uptake of adenosine by isolated bovine cortex microvessels. Neurochem. Res., 1983, 8, 1459-1469. Livemore, P.; Mitchell, G. Adenosine causes dilatation and constriction of hypothalamic blood vessels. J. Cereb. Blood Flow Metab., 1983, 3, 529-534. Edvinsson, L.; Fredholm, B. B. Characterization of adenosine receptors in isolated cerebral arteries of cat. Br. J. Pharmacol., 1983, 80, 631-637. Li, Y. O.; Fredholm, B. B. Adenosine analogues stimulate cyclic AMP formation in rabbit cerebral microvessels via adenosine A2receptors. Acta Physiol. Scand., 1985, 124, 253-259. Kalaria, R. N.; Harik, S. I. Adenosine receptors and the nucleoside transporter in human brain vasculature. J. Cereb. Blood Flow Metab., 1988, 8, 32-39. McBean, D. E.; Harper, A. M.; Rudolphi, K. A. Effects of adenosine and its analogues on porcine basilar arteries: are only A2 receptors involved? J. Cereb. Blood Flow Metab., 1988, 8, 40-45. Torregrosa, G.; Salom, J. B.; Miranda, F. J.; Alabadi, J. A.; Alvarez, C.; Alborch, E. Adenosine A2 receptors mediate cerebral vasodilation in the conscious goat. Blood Vessels, 1990, 27, 24-27. Ibayashi, S.; Ngai, A. C.; Meno, J. R.; Winn, H. R. Effects of topical adenosine analogs and forskolin on rat pial arterioles in vivo. J. Cereb. Blood Flow Metab., 1991, 11, 72-76. Coney, A. M.; Marshall, J. M. Role of adenosine and its receptors in the vasodilatation induced in the cerebral cortex of the rat by systemic hypoxia. J. Physiol., 1998, 509, 507-518. Shin, H. K.; Park, S. N.; Hong, K. W. Implication of adenosine A2A receptors in hypotension-induced vasodilation and cerebral blood flow autoregulation in rat pial arteries. Life Sci., 2000, 67, 1435-1445. Ngai, A. C.; Coyne, E. F.; Meno, J. R.; West, G. A.; Winn, H. R. Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles, Am J. Physiol. Heart Circ. Physiol., 2001, 280, H2329-2335. Shin, H. K.; Shin, Y. W.; Hong, K. W. Role of adenosine A2B receptors in vasodilation of rat pial artery and cerebral blood flow autoregulation, Am J. Physiol. Heart Circ. Physiol., 2000, 278, H339-344. Iliff, J. J.; D'Ambrosio, R.; Ngai, A. C.; Winn, H. R. Adenosine receptors mediate glutamate-evoked arteriolar dilation in the rat cerebral cortex, Am J. Physiol. Heart Circ. Physiol., 2003, 284, H1631-1637. Di Tullio, M. A.; Tayebati, S. K.; Amenta, F. Identification of adenosine A1 and A3 receptor subtypes in rat pial and intracerebral arteries. Neurosci. Lett., 2004, 366, 48-52.

1004 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 8 [428] [429]

[430] [431]

[432] [433]

[434]

[435] [436]

[437]

[438]

[439]

[440] [441]

[442]

[443] [444]

[445]

[446] [447]

[448]

[449]

Hardebo, J. E.; Kahrstrom, J.; Owman, C. P1- and P2-purine receptors in brain circulation. Eur. J. Pharmacol., 1987, 144, 343-352. Urquilla, P. R.; Van Dyke, K.; Trush, M. Structure-activity relation of pyrimidine nucleotides and nucleoside in canine isolated cerebral vessels. J. Pharm. Pharmacol., 1978, 30, 189-190. Shirasawa, Y.; White, R. P.; Robertson, J. T. Mechanisms of the contractile effect induced by uridine 5-triphosphate in canine cerebral arteries. Stroke, 1983, 14, 347-355. von Kugelgen, I.; Starke, K. Evidence for two separate vasoconstriction-mediating nucleotide receptors, both distinct from the P2x-receptor, in rabbit basilar artery: a receptor for pyrimidine nucleotides and a receptor for purine nucleotides. Naunyn Schmiedebergs Arch. Pharmacol., 1990, 341, 538-546. Laing, R. J.; Jakubowski, J.; Morice, A. H. An in vitro study of the Pharmacological responses of rat middle cerebral artery: effects of overnight storage. J. Vasc Res., 1995, 32, 230-236. Lewis, C. J.; Ennion, S. J.; Evans, R. J. P2 purinoceptor-mediated control of rat cerebral (pial) microvasculature; contribution of P2X and P2Y receptors. J. Physiol., 2000, 527, Pt 2, 315-324. Lacza, Z.; Kaldi, K.; Kovecs, K.; Gorlach, C.; Nagy, Z.; Sandor, P.; Benyo, Z.; Wahl, M. Involvement of prostanoid release in the mediation of UTP-induced cerebrovascular contraction in the rat. Brain Res., 2001, 896, 169-174. Malmsjo, M.; Hou, M.; Pendergast, W.; Erlinge, D.; Edvinsson, L. Potent P2Y6 receptor mediated contractions in human cerebral arteries. BMC Pharmacol., 2003, 3, 4. Malmsjo, M.; Hou, M.; Pendergast, W.; Erlinge, D.; Edvinsson, L. The stable pyrimidines UDPS and UTPS discriminate between contractile cerebrovascular P2 receptors. Eur. J. Pharmacol., 2003, 458, 305-311. Kamishima, T.; Quayle, J. M. P2 receptor-mediated Ca2+ transients in rat cerebral artery smooth muscle cells, Am. J. Physiol. Heart Circ. Physiol., 2004, 286, H535-544. Zhao, G.; Adebiyi, A.; Blaskova, E.; Xi, Q.; Jaggar, J. H. Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca2+ signals, and vasoconstriction in cerebral arteries. Am. J. Physiol. Cell. Physiol., 2008, 295, C1376-1384. Syyong, H. T.; Yang, H. H.; Trinh, G.; Cheung, C.; Kuo, K. H.; van Breemen, C. Mechanism of asynchronous Ca2+ waves underlying agonist-induced contraction in the rat basilar artery. Br. J. Pharmacol., 2009, 156, 587-600. Miao, L. Y.; Tang, J. P.; Esposito, D. P.; Zhang, J. H. Age-related changes in P2 receptor mRNA of rat cerebral arteries. Exp. Gerontol., 2001, 37, 67-79. Mayhan, W. G.; Arrick, D. M.; Sharpe, G. M.; Sun, H. Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress. Microcirculation, 2008, 15, 225-236. Reading, S. A.; Earley, S.; Waldron, B. J.; Welsh, D. G.; Brayden, J. E. TRPC3 mediates pyrimidine receptor-induced depolarization of cerebral arteries, Am J. Physiol. Heart Circ. Physiol., 2005, 288, H2055-2061. Lee, T. J.; Chiueh, C. C.; Adams, M. Synaptic transmission of vasoconstrictor nerves in rabbit basilar artery. Eur. J. Pharmacol., 1980, 61, 55-70. Muramatsu, I.; Fujiwara, M.; Miura, A.; Shibata, S. Reactivity of isolated canine cerebral arteries to adenine nucleotides and adenosine. Pharmacology, 1980, 21, 198-205. Muramatsu, I.; Fujiwara, M.; Miura, A.; Sakakibara, Y. Possible involvement of adenine nucleotides in sympathetic neuroeffector mechanisms of dog basilar artery. J. Pharmacol. Exp. Ther., 1981, 216, 401-409. Karashima, T.; Kuriyama, H. Electrical properties of smooth muscle Cell. membrane and neuromuscular transmission in the guineapig basilar artery. Br. J. Pharmacol., 1981, 74, 495-504. Fujiwara, S.; Itoh, T.; Suzuki, H. Membrane properties and excitatory neuromuscular transmission in the smooth muscle of dog cerebral arteries. Br. J. Pharmacol., 1982, 77, 197-208. Muramatsu, I.; Fujiwara, M.; Sakakibara, Y.; Miura, A. In: Neurogenic Release and Possible Role if Atp and Related Nucleotides in Dog Cerebral Artery. Physiology and pharmacology of adenosine derivatives Eds. Y. K. J. W. Daly, J. W. Phillis, H. Shimizu & M. Ui, Raven Prss, New York. 1983, PP 173-177. Rivilla, F.; Guemes, M.; Sanchez-Ferrer, C. F.; Ibanez, C.; Salaices, M.; Marin. J. Role of presynaptic purinoceptors and cyclic AMP on the noradrenaline release in cat cerebral arteries. J. Pharm Pharmacol., 1990, 42, 481-486.


[451] [452]

[453] [454]

[455]

[456] [457]

[458]

[459]

[460]

[461]

[462]

[463]

[464]

[465]

[466]

[467] [468]

[469]

[470]

[471]

Nag, S. Ultrastructural localization of calcium-activated adenosine triphosphatase (Ca2+-ATPase) in cerebral endothelium. Lab. Invest., 1987, 57, 52-56. Hardebo, J. E.; Kahrstrom, J.; Owman, C.; Salford, L. G. Endothelium-dependent relaxation by uridine tri- and diphosphate in isolated human pial vessels. Blood Vessels, 1987, 24, 150-155. Mayhan, W. G. Endothelium-dependent responses of cerebral arterioles to adenosine 5'-diphosphate. J. Vasc. Res., 1992, 29, 353358. Brayden, J. E. Hyperpolarization and relaxation of resistance arteries in response to adenosine diphosphate. Distribution and mechanism of action. Circ. Res., 1991, 69, 1415-1420. Toda, N.; Kawakami, M.; Yamazaki, M.; Okamura, T. Comparison of endothelium-dependent responses of monkey cerebral and temporal arteries. Br. J. Pharmacol., 1991, 102, 805-810. Ikeuchi, Y.; Nishizaki, T. Dual effects of ATP on the potassium channel and intracellular Ca2+ release in smooth muscle cells of the bovine brain arteries. Biochem. Biophys. Res. Commun., 1995, 215, 1071-1077. Zhang, H.; Weir, B. K.; Marton, L. S.; Lee, K. S.; Macdonald, R. L. P2 purinoceptors in cultured bovine middle cerebral artery endothelial cells. J. Cardiovasc. Pharmacol., 1997, 30, 767-774. Nobles, M.; Revest, P. A.; Couraud, P. O.; Abbott, N. J. Characteristics of nucleotide receptors that cause elevation of cytoplasmic calcium in immortalized rat brain endothelial cells (RBE4) and in primary cultuRes. Br. J. Pharmacol., 1995, 115, 1245-1252. Miyagi, Y.; Kobayashi, S.; Nishimura, J.; Fukui, M.; Kanaide, H. Dual regulation of cerebrovascular tone by UTP: P2U receptormediated contraction and endothelium-dependent relaxation. Br. J. Pharmacol., 1996, 118, 847-856. You, J.; Johnson, T. D.; ChildRes. W. F.; Bryan, R. M. Jr. Endothelial-mediated dilations of rat middle cerebral arteries by ATP and ADP, Am J. Physiol., 1997, 273, H1472-1477. You, J.; Johnson, T. D.; Marrelli, S. P.; Mombouli, J. V.; Bryan, R. M. Jr. P2u receptor-mediated release of endothelium-derived relaxing factor/nitric oxide and endothelium-derived hyperpolarizing factor from cerebrovascular endothelium in rats. Stroke, 1999, 30, 1125-1133. You, J.; Johnson, T. D.; Marrelli, S. P.; Bryan, R. M. Jr. Functional heterogeneity of endothelial P2 purinoceptors in the cerebrovascular tree of the rat. Am. J. Physiol., 1999, 277, H893-900. Loesch, A.; Burnstock, G. Ultrastructural localisation of ATP-gated P2X2 receptor immunoreactivity in vascular endothelial cells in rat brain. Endothelium, 2000, 7, 93-98. Horiuchi, T.; Dietrich, H. H.; Hongo, K.; Dacey, R. G. Jr. Comparison of P2 receptor subtypes producing dilation in rat intracerebral arterioles. Stroke, 2003, 34, 1473-1478. Braet, K.; Aspeslagh, S.; Vandamme, W.; Willecke, K.; Martin, P. E.; Evans, W. H.; Leybaert, L. Pharmacological sensitivity of ATP release triggered by photoliberation of inositol-1,4,5-trisphosphate and zero extracellular calcium in brain endothelial cells. J. Cell. Physiol., 2003, 197, 205-213. Xu, H. L.; Ye, S.; Baughman, V. L.; Feinstein, D. L.; Pelligrino, D. A. The role of the glia limitans in ADP-induced pial arteriolar relaxation in intact and ovariectomized female rats. Am. J. Physiol. Heart Circ. Physiol., 2005, 288, H382-388. Satterwhite, C. M.; Farrelly, A. M.; Bradley, M. E. Chemotactic, mitogenic, and angiogenic actions of UTP on vascular endothelial cells. Am. J. Physiol., 1999, 276, H1091-1097. Revest, P. A.; Abbott, N. J.; Gillespie, J. I. Receptor-mediated changes in intracellular [Ca2+] in cultured rat brain capillary endothelial cells. Brain Res., 1991, 549, 159-161. Frelin, C.; Breittmayer, J. P.; Vigne, P. ADP induces inositol phosphate-independent intracellular Ca2+ mobilization in brain capillary endothelial cells. J. Biol. Chem., 1993, 268, 8787-8792. Webb, T. E.; Feolde, E.; Vigne, P.; Neary, J. T.; Runberg, A.; Frelin, C.; Barnard, E. A. The P2Y purinoceptor in rat brain microvascular endothelial cells couple to inhibition of adenylate cyclase. Br. J. Pharmacol., 1996, 119, 1385-1392. Albert, J. L.; Boyle, J. P.; Roberts, J. A.; Challiss, R. A.; Gubby, S. E.; Boarder, M. R. Regulation of brain capillary endothelial cells by P2Y receptors coupled to Ca2+, phospholipase C and mitogenactivated protein kinase. Br. J. Pharmacol., 1997, 122, 935-941. Sipos, I.; Domotor, E.; Abbott, N. J.; Adam-Vizi, V. The Pharmacology of nucleotide receptors on primary rat brain endothelial cells grown on a biological extracellular matrix: effects on intracel-


[472]

[473]

[474]

[475]

[476]

[477] [478]

[479]

[480] [481]

[482]

[483]

[484]

[485]

[486]

[487]

[488]

[489]

[490] [491] [492]

lular calcium concentration. Br. J. Pharmacol., 2000, 131, 11951203. Vigne, P.; Breittmayer, J. P.; Frelin, C. Analysis of the influence of nucleotidases on the apparent activity of exogenous ATP and ADP at P2Y1 receptors. Br. J. Pharmacol., 1998, 125, 675-680. Vigne, P.; Breittmayer, J. P.; Frelin, C. Diadenosine polyphosphates as antagonists of the endogenous P2Y1 receptor in rat brain capillary endothelial cells of the B7 and B10 clones. Br. J. Pharmacol., 2000, 129, 1506-1512. Simon, J.; Vigne, P.; Eklund, K. M.; Michel, A. D.; Carruthers, A. M.; Humphrey, P. P.; Frelin, C.; Barnard, E. A. Activity of adenosine diphosphates and triphosphates on a P2YT-type receptor in brain capillary endothelial cells. Br. J. Pharmacol., 2001, 132, 173182. Vandamme, W.; Braet, K.; Cabooter, L.; Leybaert, L. Tumour necrosis factor alpha inhibits purinergic calcium signalling in blood-brain barrier endothelial cells. J. Neurochem., 2004, 88, 411421. Schaddelee, M. P.; Voorwinden, H. L.; van Tilburg, E. W.; Pateman, T. J.; Ijzerman, A. P.; Danhof, M.; de Boer, A. G. Functional role of adenosine receptor subtypes in the regulation of blood-brain barrier permeability: possible implications for the design of synthetic adenosine derivatives. Eur. J. Pharm. Sci., 2003, 19, 13-22. Isakovic, A. J.; Abbott, N. J.; Redzic, Z. B. Brain to blood efflux transport of adenosine: blood-brain barrier studies in the rat. J. Neurochem., 2004, 90, 272-286. Murakami, H.; Ohkura, A.; Takanaga, H.; Matsuo, H.; Koyabu, N.; Naito, M.; Tsuruo, T.; Ohtani, H.; Sawada, Y. Functional characterization of adenosine transport across the BBB in mice. Int. J. Pharm., 2005, 290, 37-44. Skaper, S. D.; Debetto, P.; Giusti, P. The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J., 2010, 24, 337-345. Franke, H.; Schepper, C.; Illes, P.; Krugel, U. Involvement of P2X and P2Y receptors in microglial activation in vivo. Purinergic Signal., 2007, 3, 435-445. Tran, M. D.; Neary, J. T. Purinergic signaling induces thrombospondin-1 expression in astrocytes. Proc. Natl. Acad. Sci. USA, 2006, 103, 9321-9326. Davalos, D.; Grutzendler, J.; Yang, G.; Kim, J. V.; Zuo, Y.; Jung, S.; Littman, D. R.; Dustin, M. L.; Gan, W. B. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci., 2005, 8, 752-758. Ohsawa, K.; Irino, Y.; Nakamura, Y.; Akazawa, C.; Inoue, K.; Kohsaka, S. Involvement of P2X4 and P2Y12 receptors in ATPinduced microglial chemotaxis. Glia, 2007, 55, 604-616. Zhang, Z.; Artelt, M.; Burnet, M.; Trautmann, K.; Schluesener, H. J. Lesional accumulation of P2X4 receptor+ monocytes following experimental traumatic brain injury. Exp. Neurol., 2006, 197, 252257. Bianco, F.; Ceruti, S.; Colombo, A.; Fumagalli, M.; Ferrari, D.; Pizzirani, C.; Matteoli, M.; Di Virgilio, F.; Abbracchio, M. P.; Verderio, C. A role for P2X7 in microglial proliferation. J. Neurochem., 2006, 99, 745-758. Neary, J. T.; Kang, Y.; Shi, Y. F.; Tran, M. D.; Wanner, I. B. P2 receptor signalling, proliferation of astrocytes, and expression of molecules involved in cell-Cell. interactions. Novartis Found. Symp., 2006, 276, 131-143. Washburn, K. B.; Neary, J. T. P2 purinergic receptors signal to STAT3 in astrocytes: Difference in STAT3 responses to P2Y and P2X receptor activation. Neuroscience, 2006, 142, 411-423. Brambilla, R.; Burnstock, G.; Bonazzi, A.; Ceruti, S.; Cattabeni, F.; Abbracchio, M. P. Cyclo-oxygenase-2 mediates P2Y receptorinduced reactive astrogliosis. Br. J. Pharmacol., 1999, 126, 563567. Florenzano, F.; Viscomi, M. T.; Cavaliere, F.; Volonte, C.; Molinari, M. Cerebellar lesion up-regulates P2X1 and P2X2 purinergic receptors in precerebellar nuclei. Neuroscience, 2002, 115, 425434. Franke, H.; Krugel, U.; Illes, P. P2 receptors and neuronal injury. Pflugers Arch., 2006, 452, 622-644. Arthur, D. B.; Georgi, S.; Akassoglou, K.; Insel, P. A. Inhibition of apoptosis by P2Y2 receptor activation: novel pathways for neuronal survival. J. Neurosci., 2006, 26, 3798-3804. Chorna, N. E.; Santiago-Perez, L. I.; Erb, L.; Seye, C. I.; Neary, J. T.; Sun, G. Y.; Weisman, G. A.; Gonzalez, F. A. P2Y receptors ac-


[493] [494]

[495]

[496]

[497] [498]

[499]

[500] [501]

[502] [503]

[504]

[505] [506]

[507] [508]

[509]

[510]

[511]

[512]

[513]

1005

tivate neuroprotective mechanisms in astrocytic cells. J. Neurochem., 2004, 91, 119-132. Inoue, K. ATP receptors for the protection of hippocampal functions, Jpn J. Pharmacol., 1998, 78, 405-410. Franke, H.; Grummich, B.; Hartig, W.; Grosche, J.; Regenthal, R.; Edwards, R. H.; Illes, P.; Krugel, U. Changes in purinergic signaling after cerebral injury - involvement of glutamatergic mechanisms? Int. J. Dev. Neurosci., 2006, 24, 123-132. Ortega, F.; Perez-Sen, R.; Delicado, E. G.; Miras-Portugal, M. T. P2X7 nucleotide receptor is coupled to GSK-3 inhibition and neuroprotection in cerebellar granule neurons. Neurotox Res., 2009, 15, 193-204. Hasche, A.; Ferenz, K. B.; Rose, K.; Konig, S.; Humpf, H. U.; Klumpp, S.; Krieglstein. J. Binding of ATP to nerve growth factor: Characterization and relevance for bioactivity. Neurochem. Int., 2010, 56(2),276-284 Berne, R. M. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am. J. Physiol., 1963, 204, 317-322. Emerson, T. E. Jr.; Raymond, R. M. Involvement of adenosine in cerebral hypoxic hyperemia in the dog. Am. J. Physiol., 1981, 241, H134-138. Winn, H. R.; Welsh, J. E.; Rubio, R.; Berne, R. M. Changes in brain adenosine during bicuculline-induced seizuRes. in rats. Effects of hypoxia and altered systemic blood pressure. Circ. Res., 1980, 47, 568-577. Rehncrona, S.; Siesjo, B. K.; Westerberg, E. Adenosine and cyclic AMP in cerebral cortex of rats in hypoxia, status epilepticus and hypercapnia. Acta Physiol. Scand, 1978, 104, 453-463. Heistad, D. D.; Marcus, M. L.; Gourley, J. K.; Busija, D. W. Effect of adenosine and dipyridamole on cerebral blood flow. Am. J. Physiol., 1981, 240, H775-780. Pinard, E.; Puiroud, S.; Seylaz. J. Role of adenosine in cerebral hypoxic hyperemia in the unanesthetized rabbit. Brain Res., 1989, 481, 124-130. Phillis, J. W.; O'Regan, M. H.; Perkins, L. M. Adenosine 5'triphosphate release from the normoxic and hypoxic in vivo rat cerebral cortex. Neurosci. Lett., 1993, 151, 94-96. Burnstock, G. Adenine nucleotides and nucleosides in cerebral hypoxia. In: Cerebral Hypoxia in the Pathogenesis of Migraine. Progress in Neurobiology Series. Eds. Rose, F. C.; Amery, W. K. Pitman Press, Bath. 1982, PP 77-81. Phillis, J. W. Adenosine and adenine nucleotides as regulators of cerebral blood flow: roles of acidosis. Cell. swelling, and KATP channels. Crit. Rev. Neurobiol., 2004, 16, 237-270. Phillis, J. W.; DeLong, R. E. An involvement of adenosine in cerebral blood flow regulation during hypercapnia. Gen. Pharmacol., 1987, 18, 133-139. Sebastião, A. M.; de Mendonça, A.; Ribeiro, J. A. Neuroprotection during hypoxic insults: role of adenosine. Drug Dev. Res., 2001, 52, 291-295. Li, X.; Zhou, T.; Zhi, X.; Zhao, F.; Yin, L.; Zhou, P. Effect of hypoxia/reoxygenation on CD73 (ecto-5'-nucleotidase) in mouse microvessel endothelial cell lines. Microvasc. Res., 2006, 72, 4853. Sperlagh, B.; Zsilla, G.; Baranyi, M.; Illes, P.; Vizi, E. S. Purinergic modulation of glutamate release under ischemic-like conditions in the hippocampus. Neuroscience, 2007, 149, 99-111. Aihara, H.; Fujiwara, S.; Mizuta, I.; Tada, H.; Kanno, T.; Tozaki, H.; Nagai, K.; Yajima, Y.; Inoue, K.; Kondoh, T.; Motooka, Y.; Nishizaki, T. Adenosine triphosphate accelerates recovery from hypoxic/hypoglycemic perturbation of guinea pig hippocampal neurotransmission via a P2 receptor. Brain Res., 2002, 952, 31-37. Lammer, A.; GunTher. A.; Beck, A.; Krugel, U.; Kittner, H.; Schneider, D.; Illes, P.; Franke, H. Neuroprotective effects of the P2 receptor antagonist PPADS on focal cerebral ischaemia-induced injury in rats. Eur. J. Neurosci., 2006, 23, 2824-2828. Braun, N.; Zhu, Y.; Krieglstein, J.; Culmsee, C.; Zimmermann, H. Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the rat. J. Neurosci., 1998, 18, 4891-4900. Cavaliere, F.; Florenzano, F.; Amadio, S.; Fusco, F. R.; Viscomi, M. T.; D'Ambrosi, N.; Vacca, F.; Sancesario, G.; Bernardi, G.; Molinari, M.; Volonte, C. Up-regulation of P2X 2, P2X4 receptor and ischemic Cell Death: prevention by P2 antagonists. Neuroscience, 2003, 120, 85-98.


[515] [516]

[517]

[518] [519]

[520]

[521]

[522]

[523] [524]

[525]

[526] [527]

[528]

[529]

[530] [531]

[532] [533]

Wirkner, K.; Kofalvi, A.; Fischer, W.; GunTher. A.; Franke, H.; Groger-Arndt, H.; Norenberg, W.; Madarasz, E.; Vizi, E. S.; Schneider, D.; Sperlagh, B.; Illes, P. Supersensitivity of P2X receptors in cerebrocortical Cell. cultuRes. after in vitro ischemia. J. Neurochem., 2005, 95, 1421-1437. Le Feuvre, R. A.; Brough, D.; Touzani, O.; Rothwell, N. J. Role of P2X7 receptors in ischemic and excitotoxic brain injury in vivo. J. Cereb. Blood Flow Metab., 2003, 23, 381-384. Carpenter, R. C.; Miao, L.; Miyagi, Y.; Bengten, E.; Zhang, J. H. Altered expression of P2 receptor mRNAs in the basilar artery in a rat double hemorrhage model. Stroke, 2001, 32, 516-522. Miekisiak, G.; Kulik, T.; Kusano, Y.; Kung, D.; Chen, J. F.; Winn, H. R. Cerebral blood flow response in adenosine 2a receptor knockout mice during transient hypoxic hypoxia. J. Cereb. Blood Flow Metab., 2008, 28, 1656-1664. Lipton, P.; Whittingham, T. S. Reduced ATP concentration as a basis for synaptic transmission failure during hypoxia in the in vitro guinea-pig hippocampus. J. Physiol., 1982, 325, 51-65. Golding, E. M.; Steenberg, M. L.; Cherian, L.; Marrelli, S. P.; Robertson, C. S.; Bryan, R. M. Jr. Endothelial-mediated dilations following severe controlled cortical impact injury in the rat middle cerebral artery. J. Neurotrauma, 1998, 15, 635-644. Kochanek, P. M.; Hendrich, K. S.; Jackson, E. K.; Wisniewski, S. R.; Melick, J. A.; Shore, P. M.; Janesko, K. L.; Zacharia, L.; Ho, C. Characterization of the effects of adenosine receptor agonists on cerebral blood flow in uninjured and traumatically injured rat brain using continuous arterial spin-labeled magnetic resonance imaging. J. Cereb. Blood Flow Metab., 2005, 25, 1596-1612. Bo, X.; Karoon, P.; Nori, S. L.; Bardini, M.; Burnstock, G. P2X purinoceptors in postmortem human cerebral arteries. J. Cardiovasc. Pharmacol., 1998, 31, 794-799. Phillis, J. W.; Walter, G. A.; O'Regan, M. H.; Stair, R. E. Increases in cerebral cortical perfusate adenosine and inosine concentrations during hypoxia and ischemia. J. Cereb. Blood Flow Metab., 1987, 7, 679-686. Winn, H. R.; Rubio, R.; Berne, R. M. Brain adenosine production in the rat during 60 seconds of ischemia. Circ. Res., 1979, 45, 486492. Dux, E.; Fastbom, J.; Ungerstedt, U.; Rudolphi, K.; Fredholm, B. B. Protective effect of adenosine and a novel xanthine derivative propentofylline on the Cell. damage after bilateral carotid occlusion in the gerbil hippocampus. Brain Res., 1990, 516, 248-256. Miller, L. P.; Hsu, C. Therapeutic potential for adenosine receptor activation in ischemic brain injury. J. Neurotrauma, 1992, 9, S563577. Rudolphi, K. A.; Schubert, P.; Parkinson, F. E.; Fredholm, B. B. Neuroprotective role of adenosine in cerebral ischaemia. Trends Pharmacol. Sci., 1992, 13, 439-445. Pearson, T.; Damian, K.; Lynas, R. E.; Frenguelli, B. G. Sustained elevation of extracellular adenosine and activation of A1 receptors underlie the post-ischaemic inhibition of neuronal function in rat hippocampus in vitro. J. Neurochem., 2006, 97, 1357-1368. Schubert, P.; Rudolphi, K. A.; Fredholm, B. B.; Nakamura, Y. Modulation of nerve and glial function by adenosine - role in the development of ischemic damage. Int. J. Biochem., 1994, 26, 12271236. Von Lubitz, D. K.; Beenhakker, M.; Lin, R. C.; Carter, M. F.; Paul, I. A.; Bischofberger, N.; Jacobson, K. A. Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist. Eur. J. Pharmacol., 1996, 302, 43-48. Bischofberger, N.; Jacobson, K. A.; von Lubitz, D. K. Adenosine A1 receptor agonists as clinically viable agents for treatment of ischemic brain disorders, Ann. N. Y. Acad. Sci., 1997, 825, 23-29. Marcoli, M.; Bonfanti, A.; Roccatagliata, P.; Chiaramonte, G.; Ongini, E.; Raiteri, M.; Maura, G. Glutamate efflux from human cerebrocortical slices during ischemia: vesicular-like mode of glutamate release and sensitivity to A(2A) adenosine receptor blockade. Neuropharmacology, 2004, 47, 884-891. Gao, Y.; Phillis, J. W. CGS 15943, an adenosine A2 receptor antagonist, reduces cerebral ischemic injury in the Mongolian gerbil, Life Sci., 1994, 55, PL61-65. Bona, E.; Aden, U.; Gilland, E.; Fredholm, B. B.; Hagberg, H. Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists. Neuropharmacology, 1997, 36, 1327-1338.


[535]

[536]

[537]

[538]

[539]

[540]

[541] [542]

[543]

[544]

[545]

[546] [547]

[548]

[549]

[550]

[551]

[552]

[553] [554]

Monopoli, A.; Lozza, G.; Forlani, A.; Mattavelli, A.; Ongini, E. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport, 1998, 9, 3955-3959. Pedata, F.; Gianfriddo, M.; Turchi, D.; Melani, A. The protective effect of adenosine A2A receptor antagonism in cerebral ischemia. Neurol. Res. 2005, 27, 169-174. Stone, T. W.; Behan, W. M. Interleukin-1beta but not tumor necrosis factor-alpha potentiates neuronal damage by quinolinic acid: protection by an adenosine A2A receptor antagonist. J. Neurosci. Res., 2007, 85, 1077-1085. Chen, J. F.; Huang, Z.; Ma, J.; Zhu, J.; Moratalla, R.; Standaert, D.; Moskowitz, M. A.; Fink, J. S.; Schwarzschild, M. A. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci., 1999, 19, 9192-9200. Aden, U.; Halldner, L.; Lagercrantz, H.; Dalmau, I.; Ledent, C.; Fredholm, B. B. Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice. Stroke, 2003, 34, 739744. Olsson, T.; Cronberg, T.; Rytter, A.; Asztely, F.; Fredholm, B. B.; Smith, M. L.; Wieloch, T. Deletion of the adenosine A1 receptor gene does not alter neuronal damage following ischaemia in vivo or in vitro. Eur. J. Neurosci., 2004, 20, 1197-1204. Von Lubitz, D. K.; Lin, R. C.; Boyd, M.; Bischofberger, N.; Jacobson, K. A. Chronic administration of adenosine A3 receptor agonist and cerebral ischemia: neuronal and glial effects. Eur. J. Pharmacol., 1999, 367, 157-163. Von Lubitz, D. K.; Lin, R. C.; Popik, P.; Carter, M. F.; Jacobson, K. A. Adenosine A3 receptor stimulation and cerebral ischemia. Eur. J. Pharmacol., 1994, 263, 59-67. Chen, G. J.; Harvey, B. K.; Shen, H.; Chou, J.; Victor, A.; Wang, Y. Activation of adenosine A3 receptors reduces ischemic brain injury in rodents. J. Neurosci. Res., 2006, 84, 1848-1855. Haun, S. E.; Segeleon, J. E.; Trapp, V. L.; Clotz, M. A.; Horrocks, L. A. Inosine mediates the protective effect of adenosine in rat astrocyte cultuRes. subjected to combined glucose-oxyGen. deprivation. J. Neurochem., 1996, 67, 2051-2059. Centonze, D.; Saulle, E.; Pisani, A.; Bernardi, G.; Calabresi, P. Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia. Brain, 2001, 124, 18551865. Zhou, A. M.; Li, W. B.; Li, Q. J.; Liu, H. Q.; Feng, R. F.; Zhao, H. G. A short cerebral ischemic preconditioning up-regulates adenosine receptors in the hippocampal CA1 region of rats. Neurosci. Res., 2004, 48, 397-404. Lai, D. M.; Tu, Y. K.; Liu, I. M.; Cheng, J. T. Increase of adenosine A1 receptor gene expression in cerebral ischemia of Wistar rats. Neurosci. Lett., 2005, 387, 59-61. Pedata, F.; Melani, A.; Pugliese, A. M.; Coppi, E.; Cipriani, S.; Traini, C. The role of ATP and adenosine in the brain under normoxic and ischemic conditions. Purinergic Signal., 2007, 3, 299310. Sato, M.; Paschen, W.; Pawlik, G.; Heiss, W. D. Neurologic deficit and cerebral ATP depletion after temporary focal ischemia in cats. J. Cereb. Blood Flow Metab., 1984, 4, 173-177. Phillis, J. W.; Walter, G. A.; Simpson, R. E. Release of purines and neurotransmitter amino acids into cerebral cortical perfusates during and following transient ischaemic. Int. J. Purine Pyrimidine Res., 1991, 2, 41-46. Chitolina Schetinger, M. R.; Bonan, C. D.; Schierholt, R. C.; Webber, A.; Arteni, N.; Emanuelli, T.; Dias, R. D.; Freitas Sarkis, J. J.; Netto, C. A. Nucleotide hydrolysis in rats submitted to global cerebral ischemia: a possible link between preconditioning and adenosine production. J. Stroke Cerebrovasc. Dis., 1998, 7, 281-286. Marrelli, S. P.; Khorovets, A.; Johnson, T. D.; ChildRes. W. F.; Bryan, R. M. Jr. P2 purinoceptor-mediated dilations in the rat middle cerebral artery after ischemia-reperfusion. Am. J. Physiol., 1999, 276, H33-41. Chen, M.; Simard, J. M. Cell. swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J. Neurosci., 2001, 21, 6512-6521. Kharlamov, A.; Jones, S. C.; Kim, D. K. Suramin reduces infarct volume in a model of focal brain ischemia in rats. Exp. Brain Res., 2002, 147, 353-359. Runden-Pran, E.; Tanso, R.; Haug, F. M.; Ottersen, O. P.; Ring, A. Neuroprotective effects of inhibiting N-methyl-D-aspartate recep-


[555]

[556]

[557]

[558]

[559]

[560]

[561]

[562]

[563]

[564]

[565]

[566]

[567] [568] [569] [570] [571]

[572]

[573] [574] [575]

tors, P2X receptors and the mitogen-activated protein kinase cascade: a quantitative analysis in organotypical hippocampal slice cultuRes. subjected to oxyGen. and glucose deprivation. Neuroscience, 2005, 136, 795-810. Wang, L. Y.; Cai, W. Q.; Chen, P. H.; Deng, Q. Y.; Zhao, C. M. Downregulation of P2X7 receptor expression in rat oligodendrocyte precursor cells after hypoxia ischemia. Glia, 2009, 57, 307319. Kim, D. S.; Kwak, S. E.; Kim, J. E.; Won, M. H.; Kang, T. C. The co-treatments of vigabatrin and P2X receptor antagonists protect ischemic neuronal Cell Death in the gerbil hippocampus. Brain Res., 2006, 1120, 151-160. Coppi, E.; Pugliese, A. M.; Stephan, H.; Muller, C. E.; Pedata, F. Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices. Purinergic Signal., 2007, 3, 203-219. Frenguelli, B. G.; Wigmore, G.; Llaudet, E.; Dale, N. Temporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampus. J. Neurochem., 2007, 101, 1400-1413. Schock, S. C.; Munyao, N.; Yakubchyk, Y.; Sabourin, L. A.; Hakim, A. M.; Ventureyra, E. C.; Thompson, C. S. Cortical spreading depression releases ATP into the extracellular space and purinergic receptor activation contributes to the induction of ischemic tolerance. Brain Res., 2007, 1168, 129-138. Pignataro, G.; Maysami, S.; Studer, F. E.; Wilz, A.; Simon, R. P.; Boison, D. Downregulation of hippocampal adenosine kinase after focal ischemia as potential endogenous neuroprotective mechanism. J. Cereb. Blood Flow Metab., 2008, 28, 17-23. Wang, Y.; Chang, C. F.; Morales, M.; Chiang, Y. H.; Harvey, B. K.; Su, T. P.; Tsao, L. I.; Chen, S.; Thiemermann, C. Diadenosine tetraphosphate protects against injuries induced by ischemia and 6hydroxydopamine in rat brain. J. Neurosci., 2003, 23, 7958-7965. Ralevic, V.; Hoyle, C. H.; Burnstock, G. Pivotal role of phosphate chain length in vasoconstrictor versus vasodilator actions of adenine dinucleotides in rat mesenteric arteries. J. Physiol., 1995, 483, 703-713. Chen, H. H.; Schock, S. C.; Xu, J.; Safarpour, F.; Thompson, C. S.; Stewart, A. F. Extracellular ATP-dependent upregulation of the transcription cofactor LMO4 promotes neuron survival from hypoxia. Exp. Cell. Res., 2007, 313, 3106-3116. Briede, J.; Duburs, G. Protective effect of cerebrocrast on rat brain ischaemia induced by occlusion of both common carotid arteries. Cell. Biochem. Funct., 2007, 25, 203-210. Lucas, S. M.; Rothwell, N. J.; Gibson, R. M. The role of inflammation in CNS injury and disease. Br. J. Pharmacol., 2006, 147, S232-240. Bours, M. J.; Swennen, E. L.; Di Virgilio, F.; Cronstein, B. N.; Dagnelie, P. C. Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther., 2006, 112, 358-404. Sperlagh, B.; Illes, P. Purinergic modulation of microglial Cell. activation. Purinergic Signal., 2007, 3, 117-127. MArch.and, F.; Perretti, M.; McMahon, S. B. Role of the immune system in chronic pain. Nat. Rev. Neurosci., 2005, 6, 521-532. Moalem, G.; Tracey, D. J. Immune and inflammatory mechanisms in neuropathic pain. Brain Res. Rev., 2006, 51, 240-264. Ferrari, D.; Stroh, C.; Schulze-Osthoff, K. P2X7/P2Z purinoreceptor-mediated activation of transcription factor NFAT in microglial cells. J. Biol. Chem., 1999, 274, 13205-13210. Potucek, Y. D.; Crain, J. M.; Watters, J. J. Purinergic receptors modulate MAP kinases and transcription factors that control microglial inflammatory gene expression. Neurochem. Int., 2006, 49, 204-214. Martinon, F.; Burns, K.; Tschopp. J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-. Mol. Cell, 2002, 10, 417-426. Di Virgilio, F. Liaisons dangereuses: P2X7 and the inflammasome. Trends Pharmacol. Sci., 2007, 28, 465-472. Suzuki, T.; Hide, I.; Ido, K.; Kohsaka, S.; Inoue, K.; Nakata, Y. Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J. Neurosci., 2004, 24, 1-7. Lemaire, I.; Falzoni, S.; Leduc, N.; Zhang, B.; Pellegatti, P.; Adinolfi, E.; Chiozzi, P.; Di Virgilio, F. Involvement of the purinergic P2X7 receptor in the formation of multinucleated giant cells. J. Immunol., 2006, 177, 7257-7265.


[577]

[578] [579]

[580]

[581]

[582]

[583] [584]

[585]

[586]

[587]

[588]

[589]

[590]

[591] [592]

[593] [594]

[595]

1007

Takenouchi, T.; Iwamaru, Y.; Imamura, M.; Kato, N.; Sugama, S.; Fujita, M.; Hashimoto, M.; Sato, M.; Okada, H.; Yokoyama, T.; Mohri, S.; Kitani, H. Prion infection correlates with hypersensitivity of P2X7 nucleotide receptor in a mouse microglial Cell. line. FEBS Lett., 2007, 581, 3019-3026. Takenouchi, T.; Sato, M.; Kitani, H. Lysophosphatidylcholine potentiates Ca2+ influx, pore formation and p44/42 MAP kinase phosphorylation mediated by P2X7 receptor activation in mouse microglial cells. J. Neurochem., 2007, 102, 1518-1532. Guo, L. H.; Trautmann, K.; Schluesener, H. J. Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain. J. Neuroimmunol., 2005, 163, 120-127. Raouf, R.; Chabot-Dore, A. J.; Ase, A. R.; Blais, D.; Seguela, P. Differential regulation of microglial P2X4 and P2X7 ATP receptors following LPS-induced activation. Neuropharmacology, 2007, 53, 496-504. Abbracchio, M. P.; Verderio, C. Pathophysiological roles of P2 receptors in glial cells. Novartis Found. Symp., 2006, 276, 91-103; discussion 103-112, 275-181. Neary, J. T.; Kang, Y.; Tran, M.; Feld. J. Traumatic injury activates protein kinase B/Akt in cultured astrocytes: role of extracellular ATP and P2 purinergic receptors. J. Neurotrauma, 2005, 22, 491500. Dorneles, A. G.; Menezes, C.; Sperotto, R. L.; Duarte, M. M.; Morsch, V. M.; Schetinger, M. R.; Loro, V. L. Adenine nucleotide hydrolysis in patients with aseptic and bacterial meningitis. Neurochem. Res., 2009, 34, 463-469. Schwarzschild, M. A. Adenosine A2A antagonists as neurotherapeutics: crossing the bridge. Prog. Neurobiol., 2007, 83, 261-262. Jun, D.; Kim, K. ATP-mediated necrotic volume increase (NVI) in substantia nigra pars compacta dopaminergic neuron. Soc. Neurosci. Abs. Book, 2004, 222.218. Heine, C.; Wegner, A.; Grosche, J.; Allgaier, C.; Illes, P.; Franke, H. P2 receptor expression in the dopaminergic system of the rat brain during development. Neuroscience, 2007, 149, 165-181. Morales, I.; Dopico, J. G.; Sabate, M.; Gonzalez-Hernandez, T.; Rodriguez, M. Substantia nigra osmoregulation: taurine and ATP involvement. Am. J. Physiol. Cell. Physiol., 2007, 292, C19341941. Xu, J.; Chalimoniuk, M.; Shu, Y.; Simonyi, A.; Sun, A. Y.; Gonzalez, F. A.; Weisman, G. A.; Wood, W. G.; Sun, G. Y. Prostaglandin E2 production in astrocytes: regulation by cytokines, extracellular ATP, and oxidative agents. Prostaglandins Leukot. Essent. Fatty Acids, 2003, 69, 437-448. McLarnon, J. G.; Ryu, J. K.; Walker, D. G.; Choi, H. B. Upregulated expression of purinergic P2X7 receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus. J. Neuropathol. Exp. Neurol., 2006, 65, 10901097. Parvathenani, L. K.; Tertyshnikova, S.; Greco, C. R.; Roberts, S. B.; Robertson, B.; Posmantur, R. P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease. J. Biol. Chem., 2003, 278, 13309-13317. Rampe, D.; Wang, L.; Ringheim, G. E. P2X7 receptor modulation of beta-amyloid- and LPS-induced cytokine secretion from human macrophages and microglia. J. Neuroimmunol., 2004, 147, 56-61. Ryu, J. K.; McLarnon, J. G. Block of purinergic P2X7 receptor is neuroprotective in an animal model of Alzheimer's disease. Neuroreport, 2008, 19, 1715-1719. Tumini, E.; Porcellini, E.; Chiappelli, M.; Conti, C. M.; Beraudi, A.; Poli, A.; Caciagli, F.; Doyle, R.; Conti, P.; Licastro, F. The G51S purine nucleoside phosphorylase polymorphism is associated with cognitive decline in Alzheimer's disease patients. Hum. Psychopharmacol., 2007, 22, 75-80. Moore, D.; Iritani, S.; Chambers, J.; Emson, P. Immunohistochemical localization of the P2Y1 purinergic receptor in Alzheimer's disease. Neuroreport, 2000, 11, 3799-3803. Camden, J. M.; Schrader, A. M.; Camden, R. E.; Gonzalez, F. A.; Erb, L.; Seye, C. I.; Weisman, G. A. P2Y2 nucleotide receptors enhance -secretase-dependent amyloid precursor protein processing. J. Biol. Chem., 2005, 280, 18696-18702. Lai, M. K.; Tan, M. G.; Kirvell, S.; Hobbs, C.; Lee, J.; Esiri, M. M.; Chen, C. P.; Francis, P. T. Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer's disease neuropathology. J. Neural Transm., 2008, 115, 1165-1172.


[597]

[598]

[599]

[600]

[601]

[602]

[603]

[604]

[605]

[606]

[607]

[608] [609]

[610]

[611] [612]

[613]

Wurtman, R. J.; Cansev, M.; Ulus, I. H. Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J. Nutr. Health Aging, 2009, 13, 189-197. McLarnon, J. G.; Choi, H. B.; Lue, L. F.; Walker, D. G.; Kim, S. U. Perturbations in calcium-mediated signal transduction in microglia from Alzheimer's disease patients. J. Neurosci. Res., 2005, 81, 426-435. Schmidt, C.; Lepsverdize, E.; Chi, S. L.; Das, A. M.; Pizzo, S. V.; Dityatev, A.; Schachner, M. Amyloid precursor protein and amyloid -peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Mol. Psychiatry, 2008, 13, 953-969. Misiti, F.; Orsini, F.; Clementi, M. E.; Masala, D.; Tellone, E.; Galtieri, A.; Giardina, B. Amyloid peptide inhibits ATP release from human erythrocytes. Biochem. Cell. Biol., 2008, 86, 501-508. Diaz-Hernandez, M.; Diez-Zaera, M.; Sanchez-Nogueiro, J.; Gomez-Villafuertes, R.; Canals, J. M.; Alberch, J.; Miras-Portugal, M. T.; Lucas, J. J. Altered P2X7-receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration. FASEB J., 2009, 23, 1893-1906. Bauer, A.; Zilles, K.; Matusch, A.; Holzmann, C.; Riess, O.; von Horsten, S. Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation. J. Neurochem., 2005, 94, 639-650. Popoli, P.; Blum, D.; Martire, A.; Ledent, C.; Ceruti, S.; Abbracchio, M. P. Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease. Prog. Neurobiol., 2007, 81, 331-348. Andries, M.; Van Damme, P.; Robberecht, W.; Van Den Bosch, L. Ivermectin inhibits AMPA receptor-mediated excitotoxicity in cultured motor neurons and extends the life span of a transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis., 2007, 25, 8-16. Kassa, R. M.; Bentivoglio, M.; Mariotti, R. Changes in the expression of P2X1 and P2X2 purinergic receptors in facial motoneurons after nerve lesions in rodents and correlation with motoneuron degeneration. Neurobiol. Dis., 2007, 25, 121-133. Casanovas, A.; Hernandez, S.; Tarabal, O.; Rossello, J.; Esquerda, J. E. Strong P2X4 purinergic receptor-like immunoreactivity is selectively associated with degenerating neurons in transgenic rodent models of amyotrophic lateral sclerosis. J. Comp Neurol., 2008, 506, 75-92. Cox, D. J.; Kovatchev, B. P.; Gonder-Frederick, L. A.; Summers, K. H.; McCall, A.; Grimm, K. J.; Clarke, W. L. Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care, 2005, 28, 71-77. Trudeau, F.; Gagnon, S.; Massicotte, G. Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus. Eur. J. Pharmacol., 2004, 490, 177-186. Duarte, J. M.; Oses, J. P.; Rodrigues, R. J.; Cunha, R. A. Modification of purinergic signaling in the hippocampus of streptozotocininduced diabetic rats. Neuroscience, 2007, 149, 382-391. Spanevello, R. M.; Mazzanti, C. M.; Kaizer, R.; Zanin, R.; Cargnelutti, D.; Hannel, L.; Correa, M.; Mazzanti, A.; Festugatto, R.; Graca, D.; Schetinger, M. R.; Morsch, V. M. Apyrase and 5'nucleotidase activities in synaptosomes from the cerebral cortex of rats experimentally demyelinated with ethidium bromide and treated with interferon-. Neurochem. Res., 2006, 31, 455-462. Guo, L. H.; Schluesener, H. J. Lesional accumulation of P2X4 receptor+ macrophages in rat CNS during experimental autoimmune encephalomyelitis. Neuroscience, 2005, 134, 199-205. Chen, L.; Brosnan, C. F. Exacerbation of experimental autoimmune encephalomyelitis in P2X7R-/- mice: evidence for loss of apoptotic activity in lymphocytes. J. Immunol., 2006, 176, 3115-3126. Lavrnja, I.; Bjelobaba, I.; Stojiljkovic, M.; Pekovic, S.; MostaricaStojkovic, M.; Stosic-Grujicic, S.; Nedeljkovic, N. Time-course changes in ectonucleotidase activities during experimental autoimmune encephalomyelitis. Neurochem. Int., 2009, 55, 193-198. Borsellino, G.; Kleinewietfeld, M.; Di Mitri, D.; Sternjak, A.; Diamantini, A.; Giometto, R.; Hopner, S.; Centonze, D.; Bernardi, G.; Dell'Acqua, M. L.; Rossini, P. M.; Battistini, L.; Rotzschke, O.; Falk, K. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood, 2007, 110, 1225-1232.


[615]

[616]

[617]

[618] [619]

[620]

[621] [622]

[623]

[624]

[625]

[626]

[627]

[628] [629]

[630]

[631]

[632]

Amadio, S.; Montilli, C.; Magliozzi, R.; Bernardi, G.; Reynolds, R.; Volonte, C. P2Y12 receptor protein in cortical gray matter lesions in multiple sclerosis. Cereb. Cortex, 2009, 20(6),1263-1273. Chen, Y.; Wu, H.; Wang, S.; Koito, H.; Li, J.; Ye, F.; Hoang, J.; Escobar, S. S.; Gow, A.; Arnett, H. A.; Trapp, B. D.; Karandikar, N. J.; Hsieh, J.; Lu, Q. R. The oligodendrocyte-specific G proteincoupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat. Neurosci., 2009, 12, 1398-1406. Zeraati, M.; Mirnajafi-Zadeh, J.; Fathollahi, Y.; Namvar, S.; Rezvani, M. E. Adenosine A1 and A2A receptors of hippocampal CA1 region have opposite effects on piriform cortex kindled seizuRes. in rats. Seizure, 2006, 15, 41-48. Knutsen, L. J. S.; Murray, T. F. Adenosine and ATP in epilepsy. In: Purinergic Approaches in Experimental Therapeutics Eds. Jacobson, K. A.; Jarvis, M. F. Wiley-Liss, New York. 1997, Ross, F. M.; Brodie, M. J.; Stone, T. W. Modulation by adenine nucleotides of epileptiform activity in the CA3 region of rat hippocampal slices. Br. J. Pharmacol., 1998, 123, 71-80. Vianna, E. P.; Ferreira, A. T.; Naffah-Mazzacoratti, M. G.; Sanabria, E. R.; Funke, M.; Cavalheiro, E. A.; Fernandes, M. J. Evidence that ATP participates in the pathophysiology of pilocarpine-induced temporal lobe epilepsy: fluorimetric, immunohistochemical, and Western blot studies. Epilepsia, 2002, 43 , 227229. Rappold, P. M.; Lynd-Balta, E.; Joseph, S. A. P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain. Brain Res., 2006, 1089, 171-178. Wieraszko, A.; Seyfried, T. N. Increased amount of extracellular ATP in stimulated hippocampal slices of seizure prone mice. Neurosci. Lett., 1989, 106, 287-293. Slezia, A.; Kekesi, A. K.; Szikra, T.; Papp, A. M.; Nagy, K.; Szente, M.; Magloczky, Z.; Freund, T. F.; Juhasz, G. Uridine release during aminopyridine-induced epilepsy. Neurobiol. Dis., 2004, 16, 490-499. NicolaiDis. R.; Bruno, A. N.; Sarkis, J. J.; Souza, D. O. Increase of adenine nucleotide hydrolysis in rat hippocampal slices after seizuRes. induced by quinolinic acid. Neurochem. Res., 2005, 30, 385-390. Oses, J. P. Modification by kainate-induced convulsions of the density of presynaptic P2X receptors in the rat hippocampus. Purinergic Signal., 2006, 2, 252-253. Dona, F.; Ulrich, H.; Persike, D. S.; Conceicao, I. M.; Blini, J. P.; Cavalheiro, E. A.; Fernandes, M. J. Alteration of purinergic P2X4 and P2X7 receptor expression in rats with temporal-lobe epilepsy induced by pilocarpine. Epilepsy Res., 2009, 83, 157-167. Schetinger, M. R.; Morsch, V. M.; Bonan, C. D.; Wyse, A. T. NTPDase and 5'-nucleotidase activities in physiological and disease conditions: new perspectives for human health. Biofactors, 2007, 31, 77-98. Cognato, G. P.; Bruno, A. N.; da Silva, R. S.; Bogo, M. R.; Sarkis, J. J.; Bonan, C. D. Antiepileptic drugs prevent changes induced by pilocarpine model of epilepsy in brain ecto-nucleotidases. Neurochem. Res., 2007, 32, 1046-1055. Grosso, S.; Rocchi, R.; Margollicci, M.; Vatti, G.; Luddi, A.; MArch.i, F.; Balestri, P. Postictal serum nucleotidases activities in patients with epilepsy. Epilepsy Res., 2009, 84, 15-20. Avignone, E.; Ulmann, L.; Levavasseur, F.; Rassendren, F.; Audinat, E. Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J. Neurosci., 2008, 28, 9133-9144. Vinade, E. R.; Schmidt, A. P.; Frizzo, M. E.; Izquierdo, I.; Elisabetsky, E.; Souza, D. O. Chronically administered guanosine is anticonvulsant, amnesic and anxiolytic in mice. Brain Res., 2003, 977, 97-102. Hanna, G. L.; Veenstra-Vanderweele, J.; Cox, N. J.; Van Etten, M.; Fischer, D. J.; Himle, J. A.; Bivens, N. C.; Wu, X.; Roe, C. A.; Hennessy, K. A.; Dickel, D. E.; Leventhal, B. L.; Cook, E. H. Jr. Evidence for a susceptibility locus on chromosome 10p15 in earlyonset obsessive-compulsive disorder. Biol. Psychiatry, 2007, 62, 856-862. AleSci. S.; Martinez, P. E.; Kelkar, S.; Ilias, I.; Ronsaville, D. S.; Listwak, S. J.; Ayala, A. R.; Licinio, J.; Gold, H. K.; Kling, M. A.; Chrousos, G. P.; Gold, P. W. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its


[633] [634]

[635]

[636]

[637]

[638]

[639]

[640]

[641]

[642]

[643] [644]

[645]

[646]

[647]

[648]

[649] [650]

secretion: clinical implications. J. Clin. Endocrinol. Metab., 2005, 90, 2522-2530. Bennett, M. R. Synaptic P2X7 receptor regenerative-loop hypothesis for depression, Aust. N. Z. J. Psychiatry, 2007, 41, 563-571. Lodge, N. J.; Li, Y. W. Ion channels as potential targets for the treatment of depression. Curr. Opin. Drug Discov. Devel., 2008, 11, 633-641. Lucae, S.; Salyakina, D.; Barden, N.; Harvey, M.; Gagne, B.; Labbe, M.; Binder, E. B.; Uhr, M.; Paez-Pereda, M.; Sillaber, I.; Ising, M.; Bruckl, T.; Lieb, R.; Holsboer, F.; Muller-Myhsok, B. P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum. Mol. Genet., 2006, 15, 2438-2445. Barden, N.; Harvey, M.; Gagne, B.; Shink, E.; Tremblay, M.; Raymond, C.; Labbe, M.; Villeneuve, A.; Rochette, D.; Bordeleau, L.; Stadler, H.; Holsboer, F.; Muller-Myhsok, B. Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet., 2006, 141B, 374-382. Busnello, J. V.; Oses, J. P.; da Silva, R. S.; Feier, G.; Barichello, T.; Quevedo, J.; Bohmer, A. E.; Kapczinski, F.; Souza, D. O.; Sarkis, J. J.; Portela, L. V. Peripheral nucleotide hydrolysis in rats submitted to a model of electroconvulsive therapy, Prog. NeuropsychoPharmacol. Biol. Psychiatry, 2008, 32, 1829-1833. Basso, A. M.; Bratcher, N. A.; Harris, R. R.; Jarvis, M. F.; Decker, M. W.; Rueter, L. E. Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders. Behav. Brain Res., 2009, 198, 83-90. Pedrazza, E. L.; Rico, E. P.; Senger, M. R.; Pedrazza, L.; Zimmermann, F. F.; Sarkis, J. J.; Bogo, M. R.; Bonan, C. D. Ectonucleotidase pathway is altered by different treatments with fluoxetine and nortriptyline. Eur. J. Pharmacol., 2008, 583, 18-25. Klempan, T. A.; Sequeira, A.; Canetti, L.; Lalovic, A.; Ernst, C.; ffrench-Mullen, J.; Turecki, G. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol. Psychiatry, 2009, 14, 175-189. Zou, C. J.; Onaka, T. O.; Yagi, K. Effects of suramin on neuroendocrine and Behav.ioural responses to conditioned fear stimuli. Neuroreport, 1998, 9, 997-999. Lara, D. R.; Dall'Igna, O. P.; Ghisolfi, E. S.; Brunstein, M. G. Involvement of adenosine in the neurobiology of schizophrenia and its therapeutic implications. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2006, 30, 617-629. Lara, D. R.; Souza, D. O. Schizophrenia: a purinergic hypothesis. Med. Hypotheses, 2000, 54, 157-166. Hansen, T.; Jakobsen, K. D.; Fenger, M.; Nielsen, J.; Krane, K.; Fink-Jensen, A.; Lublin, H.; Ullum, H.; Timm, S.; Wang, A. G.; Jorgensen, N. R.; Werge, T. Variation in the purinergic P2RX7 receptor gene and schizophrenia. Schizophr. Res., 2008, 104, 146152. Seibt, K. J.; Oliveira Rda, L.; Rico, E. P.; Dias, R. D.; Bogo, M. R.; Bonan, C. D. Antipsychotic drugs inhibit nucleotide hydrolysis in zebrafish (Danio rerio) brain membranes. Toxicol. In Vitro, 2009, 23, 78-82. McQuillin, A.; Bass, N. J.; Choudhury, K.; Puri, V.; Kosmin, M.; Lawrence, J.; Curtis, D.; Gurling, H. M. Case-control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders. Mol. Psychiatry, 2009, 14, 614-620. Franke, H.; Kittner, H.; Grosche, J.; Illes, P. Enhanced P2Y1 receptor expression in the brain after sensitisation with d-amphetamine. Psychopharmacology, (Berl) 2003, 167, 187-194. Davies, D. L.; Kochegarov, A. A.; Kuo, S. T.; Kulkarni, A. A.; Woodward, J. J.; King, B. F.; Alkana, R. L. Ethanol differentially affects ATP-gated P2X3 and P2X 4 receptor subtypes expressed in Xenopus oocytes. Neuropharmacology, 2005, 49, 243-253. Burnstock, G. Purinergic P2 receptors as targets for novel analgesics. Pharmacol. Ther., 2006, 110, 433-454. Honore, P.; Kage, K.; Mikusa, J.; Watt, A. T.; Johnston, J. F.; Wyatt, J. R.; Faltynek, C. R.; Jarvis, M. F.; Lynch, K. Analgesic profile of intrathecal P2X3 antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain, 2002, 99, 11-19.


[652] [653]

[654] [655] [656] [657] [658] [659]

[660]

[661]

[662]

[663]

[664]

[665]

[666]

[667] [668] [669]

[670]

[671]

[672]

1009

Dorn, G.; Patel, S.; Wotherspoon, G.; Hemmings-Mieszczak, M.; Barclay, J.; Natt, F. J.; Martin, P.; Bevan, S.; Fox, A.; Ganju, P.; Wishart, W.; Hall. J. siRNA relieves chronic neuropathic pain. Nucleic Acids Res., 2004, 32, e49. Jo, Y. H.; Schlichter, R. Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat. Neurosci., 1999, 2, 241-245. Tsuda, M.; Shigemoto-Mogami, Y.; Koizumi, S.; Mizokoshi, A.; Kohsaka, S.; Salter, M. W.; Inoue, K. P2X 4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature, 2003, 424, 778-783. McGaraughty, S.; Jarvis, M. F. Purinergic control of neuropathic pain, Drug Dev. Res., 2006, 67, 376-388. Inoue, K. P2 receptors and chronic pain. Purinergic Signal., 2007, 3, 135-144. Scholz, J.; Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci., 2007, 10, 1361-1368. Inoue, K. ATP receptors of microglia involved in pain. Novartis Found. Symp., 2006, 276, 263-272. Trang, T.; Beggs, S.; Salter, M. W. Purinoceptors in microglia and neuropathic pain. Pflugers Arch., 2006, 452, 645-652. Coull, J. A.; Beggs, S.; Boudreau, D.; Boivin, D.; Tsuda, M.; Inoue, K.; Gravel, C.; Salter, M. W.; De Koninck, Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature, 2005, 438, 1017-1021. Nasu-Tada, K.; Koizumi, S.; Tsuda, M.; Kunifusa, E.; Inoue, K. Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X4, a key molecule for mechanical allodynia. Glia, 2006, 53, 769-775. Tsuda, M.; Mizokoshi, A.; Shigemoto-Mogami, Y.; Koizumi, S.; Inoue, K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia, 2004, 45, 89-95. Morita, K.; Morioka, N.; Abdin, J.; Kitayama, S.; Nakata, Y.; Dohi, T. Development of tactile allodynia and thermal hyperalgesia by intrathecally administered platelet-activating factor in mice. Pain, 2004, 111, 351-359. Chessell, I. P.; Hatcher, J. P.; Bountra, C.; Michel, A. D.; Hughes, J. P.; Green, P.; Egerton, J.; Murfin, M.; Richardson, J.; Peck, W. L.; Grahames, C. B.; Casula, M. A.; Yiangou, Y.; Birch, R.; Anand, P.; Buell, G. N. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain, 2005, 114, 386-396. Chessell, I. P.; Hatcher, J. P.; Hughes, J. P.; Ulmann, L.; Green, P.; Mander, P. K.; Reeve, A. J.; Rassendren, F. The role of P2X7 and P2X4 in pain processing; common or divergent pathways? Purinergic Signal., 2006, 2, 46-47. Okada, M.; Nakagawa, T.; Minami, M.; Satoh, M. Analgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats. J. Pharmacol. Exp. Ther., 2002, 303, 66-73. Ruan, H. Z.; Burnstock, G. Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochem. Cell. Biol., 2003, 120, 415-426. Gerevich, Z.; Illes, P. P2Y receptors and pain transmission. Purinergic Signal., 2004, 1, 3-10. Selden, N. R.; Carlson, J. D.; Cetas, J.; Close, L. N.; Heinricher, M. M. Purinergic actions on neurons that modulate nociception in the rostral ventromedial medulla. Neuroscience, 2007, 146, 1808-1816. Gerevich, Z.; Zadori, Z.; Muller, C.; Wirkner, K.; Schroder, W.; Rubini, P.; Illes, P. Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization. Br. J. Pharmacol., 2007, 151, 226-236. Nakagawa, T.; Wakamatsu, K.; Zhang, N.; Maeda, S.; Minami, M.; Satoh, M.; Kaneko, S. Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance. Neuroscience, 2007, 147, 445455. Ueno, S.; Moriyama, T.; Honda, K.; Kamiya, H.; Sakurada, T.; Katsuragi, T. Involvement of P2X2 and P2X 3 receptors in neuropathic pain in a mouse model of chronic constriction injury. Drug Dev. Res., 2003, 59, 104-111. Tsuda, M.; Hasegawa, S.; Inoue, K. P2X receptors-mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain. J. Neurochem., 2007, 103, 1408-1416.


[674]

[675] [676]

[677] [678] [679]

[680]

[681] [682]

[683]

[684]

[685] [686]

[687]

[688]

[689] [690]

[691]

[692]

[693]

Chen, Y.; Li, G. W.; Wang, C.; Gu, Y.; Huang, L. Y. Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. Pain, 2005, 119, 38-48. McGaraughty, S.; Honore, P.; Wismer, C. T.; Mikusa, J.; Zhu, C. Z.; McDonald, H. A.; Bianchi, B.; Faltynek, C. R.; Jarvis, M. F. Endogenous opioid mechanisms partially mediate P2X3/P2X2/3related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain. Br. J. Pharmacol., 2005, 146, 180-188. Hughes, J. P.; Hatcher, J. P.; Chessell, I. P. The role of P2X 7 in pain and inflammation. Purinergic Signal., 2007, 3, 163-169. McGaraughty, S.; Chu, K. L.; Namovic, M. T.; Donnelly-Roberts, D. L.; Harris, R. R.; Zhang, X. F.; Shieh, C. C.; Wismer, C. T.; Zhu, C. Z.; Gauvin, D. M.; Fabiyi, A. C.; Honore, P.; Gregg, R. J.; Kort, M. E.; Nelson, D. W.; Carroll, W. A.; Marsh, K.; Faltynek, C. R.; Jarvis, M. F. P2X7-related modulation of pathological nociception in rats. Neuroscience, 2007, 146, 1817-1828. McQuay, H. J.; Tramer, M.; Nye, B. A.; Carroll, D.; Wiffen, P. J.; Moore, R. A. A systematic review of antidepressants in neuropathic pain. Pain, 1996, 68, 217-227. Burnstock, G. The role of adenosine triphosphate in migraine. Biomed. Pharmacother., 1989, 43, 727-736. Ambalavanar, R.; Moritani, M.; Dessem, D. Trigeminal P2X 3 receptor expression differs from dorsal root ganglion and is modulated by deep tissue inflammation. Pain, 2005, 117, 280-291. Fabbretti, E.; D'Arco, M.; Fabbro, A.; Simonetti, M.; Nistri, A.; Giniatullin, R. Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J. Neurosci., 2006, 26, 6163-6171. Giniatullin, R.; Nistri, A.; Fabbretti, E. Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol. Neurobiol., 2008, 37, 83-90. Chen, C. C.; Akopian, A. N.; Sivilotti, L.; Colquhoun, D.; Burnstock, G.; Wood, J. N. A P2X purinoceptor expressed by a subset of sensory neurons. Nature, 1995, 377, 428-431. Fumagalli, M.; Ceruti, S.; Verderio, C.; Abbracchio, M. P. ATP as a neurotransmitter of pain in migraine: a functional role for P2Y receptors in primary cultuRes. from mouse trigeminal sensory ganglia. Purinergic Signal., 2006, 2, 120-121. D'Arco, M.; Giniatullin, R.; Simonetti, M.; Fabbro, A.; Nair, A.; Nistri, A.; Fabbretti, E. Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. J. Neurosci., 2007, 27, 8190-8201. Gever, J. R.; Cockayne, D. A.; Dillon, M. P.; Burnstock, G.; Ford, A. P. Pharmacology of P2X channels. Pflugers Arch., 2006, 452, 513-537. Carroll, W. A.; Donnelly-Roberts, D.; Jarvis, M. F. Selective P2X7 receptor antagonists for chronic inflammation and pain. Purinergic Signal., 2009, 5, 63-73. Guile, S. D.; Alcaraz, L.; Birkinshaw, T. N.; Bowers, K. C.; Ebden, M. R.; Furber, M.; Stocks, M. J. Antagonists of the P2X7 receptor. From lead identification to drug development. J. Med. Chem., 2009, 52, 3123-3141. Brotherton-Pleiss, C. E.; Dillon, M. P.; Ford, A. P.; Gever, J. R.; Carter, D. S.; Gleason, S. K.; Lin, C. J.; Moore, A. G.; Thompson, A. W.; Villa, M.; Zhai, Y. Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist. Bioorg. Med. Chem. Lett., 2010, 20, 1031-1036. Praetorius, H. A.; Leipziger. J. ATP release from non-excitable cells. Purinergic Signal., 2009, 5, 433-446. Baqi, Y.; Lee, S. Y.; Iqbal, J.; Ripphausen, P.; Lehr, A.; Scheiff, A. B.; Zimmermann, H.; Bajorath, J.; Muller, C. E. Development of potent and selective inhibitors of ecto-5'-nucleotidase based on an anthraquinone scaffold. J. Med. Chem., 2010, 53, 2076-2086. Ivanov, A. A.; Barak, D.; Jacobson, K. A. Evaluation of homology modeling of G-protein-coupled receptors in light of the A2A adenosine receptor crystallographic structure. J. Med. Chem., 2009, 52, 3284-3292. Kawate, T.; Michel, J. C.; Birdsong, W. T.; Gouaux, E. Crystal structure of the ATP-gated P2X4 ion channel in the closed state. Nature, 2009, 460, 592-598. Collo, G.; North, R. A.; Kawashima, E.; Merlo-Pich, E.; Neidhart, S.; Surprenant, A.; Buell, G. Cloning of P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATPgated ion channels. J. Neurosci., 1996, 16, 2495-2507.


[695]

[696] [697]

[698]

[699]

[700] [701]

[702]

[703]

[704]

[705] [706]

[707]

[708] [709]

[710] [711]

[712] [713]

[714]

[715]

Kidd, E. J.; Grahames, C. B.; Simon, J.; Michel, A. D.; Barnard, E. A.; Humphrey, P. P. Localization of P2X purinoceptor transcripts in the rat nervous system. Mol. Pharmacol., 1995, 48, 569-573. Simon, J.; Kidd, E. J.; Smith, F. M.; Chessell, I. P.; MurrellLagnado, R.; Humphrey, P. P.; Barnard, E. A. Localization and functional expression of splice variants of the P2X2 receptor. Mol. Pharmacol., 1997, 52, 237-248. Seguela, P.; Haghighi, A.; Soghomonian, J. J.; Cooper, E. A novel neuronal P2x ATP receptor ion channel with widespread distribution in the brain. J. Neurosci., 1996, 16, 448-455. Soto, F.; Garcia-Guzman, M.; Gomez-Hernandez, J. M.; Hollmann, M.; Karschin, C.; Stuhmer, W. P2X4: an ATP-activated ionotropic receptor cloned from rat brain. Proc. Natl. Acad. Sci. USA, 1996, 93, 3684-3688. Bo, X.; Zhang, Y.; Nassar, M.; Burnstock, G.; Schoepfer, R. A P2X purinoceptor cDNA conferring a novel Pharmacological profile. FEBS Lett., 1995, 375, 129-133. Le, K. T.; Villeneuve, P.; Ramjaun, A. R.; McPherson, P. S.; Beaudet, A.; Seguela, P. Sensory presynaptic and widespread somatodendritic immunolocalization of central ionotropic P2X ATP receptors. Neuroscience, 1998, 83, 177-190. Xiang, Z.; Bo, X.; Oglesby, I.; Ford, A.; Burnstock, G. Localization of ATP-gated P2X2 receptor immunoreactivity in the rat hypothalamus. Brain Res., 1998, 813, 390-397. Shibuya, I.; Tanaka, K.; Hattori, Y.; Uezono, Y.; Harayama, N.; Noguchi, J.; Ueta, Y.; Izumi, F.; Yamashita, H. Evidence that multiple P2X purinoceptors are functionally expressed in rat supraoptic neurones. J. Physiol., 1999, 514, 351-367. Vulchanova, L.; Arvidsson, U.; Riedl, M.; Wang, J.; Buell, G.; Surprenant, A.; North, R. A.; Elde, R. Differential distribution of two ATP-gated channels (P2X receptors) determined by immunocytochemistry. Proc. Natl. Acad. Sci. USA, 1996, 93, 8063-8067. Vulchanova, L.; Riedl, M. S.; Shuster, S. J.; Buell, G.; Surprenant, A.; North, R. A.; Elde, R. Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology, 1997, 36, 1229-1242. Llewellyn-Smith, I. J.; Burnstock, G. Ultrastructural localization of P2X3 receptors in rat sensory neurons. Neuroreport, 1998, 9, 25452550. Atkinson, L.; Batten, T. F.; Deuchars. J. P2X2 receptor immunoreactivity in the dorsal vagal complex and area postrema of the rat. Neuroscience, 2000, 99, 683-696. Yao, S. T.; Barden, J. A.; Finkelstein, D. I.; Bennett, M. R.; Lawrence, A. J. Comparative study on the distribution patterns of P2X1P2X6 receptor immunoreactivity in the brainstem of the rat and the common marmoset (Callithrix jacchus): association with catecholamine Cell. groups. J. Comp Neurol., 2000, 427, 485-507. Yao, S. T.; Gourine, A. V.; Spyer, K. M.; Barden, J. A.; Lawrence, A. J. Localisation of P2X2 receptor subunit immunoreactivity on nitric oxide synthase expressing neurones in the brain stem and hypothalamus of the rat: a fluorescence immunohistochemical study. Neuroscience, 2003, 121, 411-419. Thomas, T.; Spyer, K. M. ATP as a mediator of mammalian central CO2 chemoreception. J. Physiol., 2000, 523, 441-447. Ralevic, V.; Thomas, T.; Burnstock, G.; Spyer, K. M. Characterization of P2 receptors modulating neural activity in rat rostral ventrolateral medulla. Neuroscience, 1999, 94, 867-878. Tanaka, J.; Murate, M.; Wang, C. Z.; Seino, S.; Iwanaga, T. Cellular distribution of the P2X4 ATP receptor mRNA in the brain and non-neuronal organs of rats. Arch. Histol. Cytol, 1996, 59, 485-490. Bo, X.; Kim, M.; Nori, S. L.; Schoepfer, R.; Burnstock, G.; North, R. A. Tissue distribution of P2X4 receptors studied with an ectodomain antibody. Cell. Tissue Res., 2003, 313, 159-165. Worthington, R. A.; Arumugam, T. V.; Hansen, M. A.; Balcar, V. J.; Barden, J. A. Identification and localisation of ATP P2X receptors in rat midbrain. Electrophoresis, 1999, 20, 2077-2080. Soto, F.; Garcia-Guzman, M.; Karschin, C.; Stuhmer, W. Cloning and tissue distribution of a novel P2X receptor from rat brain. Biochem. Biophys. Res. Commun., 1996, 223, 456-460. Tuyau, M.; Hansen, M. A.; Coleman, M. J.; Dampney, R. A.; Balcar, V. J.; Bennett, M. R. Autoradiography of [3H],-methyleneATP binding sites in medulla oblongata and spinal cord of the rat. Neurochem. Int., 1997, 30, 159-169. Pankratov, Y.; Lalo, U.; Castro, E.; Miras-Portugal, M. T.; Krishtal, O. ATP receptor-mediated component of the excitatory synap-


[716]

[717] [718]


tic transmission in the hippocampus. Prog. Brain Res., 1999, 120, 237-249. Khakh, B. S.; Humphrey, P. P.; Henderson, G. ATP-gated cation channels (P2X purinoceptors) in trigeminal mesencephalic nucleus neurons of the rat. J. Physiol., 1997, 498, 709-715. Shen, K. Z.; North, R. A. Excitation of rat locus coeruleus neurons by adenosine 5'-triphosphate: ionic mechanism and receptor characterization. J. Neurosci., 1993, 13, 894-899. Funk, G. D.; Kanjhan, R.; Walsh, C.; Lipski, J.; Comer, A. M.; Parkis, M. A.; Housley, G. D. P2 receptor excitation of rodent hypoglossal motoneuron activity in vitro and in vivo: a molecular physiological analysis. J. Neurosci., 1997, 17, 6325-6337.

Received: February 18, 2010

Revised: May 21, 2010

Accepted: May 28, 2010

[719]

[720] [721]

[722]

1011

Furukawa, K.; Ishibashi, H.; Akaike, N. ATP-induced inward current in neurons freshly dissociated from the tuberomammillary nucleus. J. Neurophysiol., 1994, 71, 868-873. Nabekura, J.; Ueno, S.; Ogawa, T.; Akaike, N. Colocalization of ATP and nicotinic ACh receptors in the identified vagal preganglionic neurone of rat. J. Physiol., 1995, 489, 519-527. Cook, S. P.; Vulchanova, L.; Hargreaves, K. M.; Elde, R.; McCleskey, E. W. Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature, 1997, 387, 505-508. Ueno, S.; Harata, N.; Inoue, K.; Akaike, N. ATP-gated current in dissociated rat nucleus solitarii neurons. J. Neurophysiol., 1992, 68, 778-785.