Inflammatory process as a determinant factor for the degeneration of ...

DOI 10.1007/s00702-004-0121-3 J Neural Transm (2005) 112: 111–119

Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons A. J. Herrera, M. Toma´s-Camardiel, J. L. Venero, J. Cano, and A. Machado Departamento de Bioquı´mica, Bromatologıá, Toxicologıá y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Spain Received December 19, 2003; accepted January 18, 2004 Published online March 19, 2004; # Springer-Verlag 2004

Summary. The specific degeneration of dopaminergic neurons in the substantia nigra (SN) is a pathological hallmark of Parkinson’s disease (PD). Although the cause of chronic nigral cell death in PD and its underlying mechanisms remain elusive, substantial involvement of inflammatory events has been postulated since inflammatory features have been described in parkinsonians CNS tissue. We have developed an animal model of dopaminergic neurons degeneration by the single intranigral injection of lipopolysaccharide (LPS), an inflammatory compound. This single injection produced the induction of inflammatory process with the activation of microglia along with the specific degeneration of dopaminergic neurons in the SN without affecting neither other neurotransmitter systems nor other structures of the CNS. Dexamethasone, a potent antiinflammatory drug preventing many of the features characterizing pro-inflammatory glial activation, prevented the loss of dopaminergic cells. We also discuss other inductors of inflammatory process in relationship to the dopaminergic degeneration in the SN. Keywords: Inflammation, LPS, microglia, substantia nigra, dopamine, Parkinson’s disease.

Introduction Parkinson’s disease is characterized by the progressive loss of dopamine (DA) in the caudate nucleus, putamen, and substantia nigra (SN) upon the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in cardinal motor symptoms such as tremor at rest, bradikinesia, muscular rigidity,

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stooped posture, and instability. The etiology of idiopathic PD, which accounts for more than 90% of PD, is still not fully understood, although familial PD correlates with mutations of genes encoding several proteins, including a-synuclein, parkin and ubiquitin C terminal hydrolase-L1 (Mouradian, 2002). The most accepted hypothesis currently envisaged for the etiology of PD is selective oxidative stress in the SN (Jenner, 2003). This is supported by both postmortem studies and those demonstrating the capacity of oxidative stress and oxidizing toxins to induce nigral cell degeneration (Olanow et al., 1998). Impaired energy metabolism produced by mitochondrial dysfunction may also be involved in the degenerative process of PD, as suggested by an accumulating body of evidence (Jenner, 1998). The possible role of the dysfunction of the protein degradation system is also considered (McNaught and Olanow, 2003). Inflammatory features as a characteristic of the degenerative process of the nigrostriatal dopaminergic system There is increasing evidence that microglial-associated inflammation may underlie the degeneration of nigral dopaminergic neurons. Different kinds of inflammatory features have been described in parkinsonian brains: a dramatic proliferation of reactive ameboid macrophages and microglia (HLA-DR positive) was found in SN of PD patients in postmortem studies (McGeer et al., 1988; Hirsch et al., 1998), and activated glial cells expressing different pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and interferon (IFN)-g (Hunot et al., 1996, 1997, 1999; Mogi et al., 1998) and inducible nitric oxide synthase (iNOS) appear in the SN (Hunot et al., 1997; Mogi et al., 1998). Increased expression of pro-inflammatory cytokines, such as interleukin-1 and 6 (IL-1, IL-6) and TNF-a, has also been found in the cerebrospinal fluid of patients with PD (for review, see Nagatsu et al., 2000a, b; Nagatsu, 2002). All these data suggest that inflammatory events could be substantially involved in the pathogenesis of PD. Toxic animal models of PD display similar inflammatory features. A markedly increased expression of both major histocompatibility complex (MHC) class I and II antigens and upregulation of iNOS expression occurred in the striatum and SNc of mice intoxicated with MPTP (Kurkowska-Jstrzebska et al., 1999) along with the increase of proinflammatory cytokines such as IL-1b and IL-6 (Mogi et al., 1998). MPTP altered the expression of several genes involved in inflammation, like IL-1, IL-6, IL-10 and TNF-a (Mandel et al., 2003). Another animal model of PD (6-OHDA lesioned rats) also shows increased levels of TNFa in both SN and striatum (Mogi et al., 1999), along with the activation of microglia (Cicchetti et al., 2002). Extensive microglial activation occurred in striatum and SN in the rotenone model of PD in rat (Sherer et al., 2003). Induction of neuroinflammation by the intranigral injection of LPS produces the specific degeneration of the nigrostriatal dopaminergic system All these data strongly suggests some relationship between neurodegeneration and the inflammatory process. Microglial activation is the brain’s major defense

Degeneration of substantia nigra dopaminergic neurons

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against immune challenges, but it results in the release of various cytokines and free radicals such as superoxide radicals and NO (Minghetti et al., 1999). These microglial factors may increase neurotoxicity and contribute to neurodegeneration in inflammatory-mediated diseases (McGeer et al., 1988). The inflammatory process (proliferation and activation of microglia) could be an event secondary to the degenerative process occurring in dopaminergic neurons, but at the same time it could help to the progress of degeneration. Moreover, there is also the possibility that the inflammatory process itself could be deleterious for dopaminergic neurons of the nigrostriatal system. Regarding this, in vitro studies have described that dopaminergic neurons were twice as sensitive to the toxic effects of lipopolysaccharide (LPS), a potent inductor of inflammation, as were tyrosine hydroxylase (TH) negative neurons (Bronstein et al., 1995). LPS affects microglia and astrocytes (Lieberman et al., 1989; Chung and Benveniste, 1990; Benveniste, 1992) and produces the activation of glial cells in vivo after its intracerebral injection (Bourdiol et al., 1991; Andersson et al., 1992). We studied the effect of the intranigral injection of LPS on the dopaminergic system of the rat (Casta~ no et al., 1998). LPS injection (2 mg) produced the activation of microglial cells that was already obvious 2 days after injection. Moreover, there was a progressive degeneration of the dopaminergic system shown by the significant decrease in DA levels in both SN and striatum up to one year after LPS injection. This was supported by the decrease in TH activity, the rate-limiting enzyme of catecholamines biosynthesis, and the loss of TH-positive neuronal bodies. The interest of this finding would increase depending on the specificity of the LPS effect. Thus, we studied which neuronal phenotypes (dopaminergic, serotoninergic, or GABAergic) were affected after a single injection of LPS into one of four locations: SN (containing DA cells bodies), medial forebrain bundle (MFB) and striatum (terminal region) within the nigrostriatal pathway, plus dorsal raphe nuclei (DR), where 5-hydroxytryptamine (5-HT) neurons are located (Herrera et al., 2000). We found that 2 mg of LPS induced a strong macrophage= microglial reaction in SN, with a characteristic clustering of macrophage cells around blood vessels. The SN was far more sensitive than the other structures studied (striatum and raphe). Similar results were found by Kim et al. (2000) which used 5–10 mg of LPS to study its effect also on hippocampus and cortex. The special susceptibility of SN could be due to specific structural differences between SN and the other areas. For instance, SN has the highest concentration of microglia in the brain (Lawson et al., 1990). The different biochemical and immunocytochemical parameters studied showed that the injection of LPS into either the MFB or the striatum did not affect the DA system. Moreover, only the dopaminergic neurons of the SN were affected. Our results showed that LPS did not induce damage to GABAergic neurons as was indicated by the unaltered transcription of glutamic acid decarboxylase (GAD) mRNA after LPS injection in the SN or the striatum. Similarly, LPS injection into the DR did not change the immunostaining of serotoninergic cells. The damage to DA neurons in SN was permanent, as observed 1 year postinjection. Kim et al. (2000) also found that the mesencephalic cultures were more sensitive to LPS at a concentration as low as 10 mg=ml and responded in a dose-dependent manner

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Fig. 1. Neuron-glia interactions that may lead to neuronal death. Inflammation may be directly induced by several ‘‘external’’ factors such as stroke, infection or trauma, which may also disrupt the blood brain barrier (BBB) with the consequent extravasation of compounds that may activate microglial cells and lead to the formation of radical oxygen species (ROS). In addition, activated microglia release several compounds, as proinflammatory cytokines, NO and ROS, that may lead to neuronal death. Within the dopaminergic neuron, the mitochondrial respiratory chain can be affected by toxins and inhibitors, leading to energy failure, production of ROS and reduction of the viability of the neurons. These ROS may act as a signal for the activation of microglial cells, indicating neurons are not healthy. Dopamine (DA) can exert a toxic action through its oxidative metabolites, forming ROS. DA may also form complexes with cysteine, inhibiting the mitochondrial respiratory chain and producing more ROS. Inhibition of the microglial activation would be one of the most important factors in the prevention of the neurodegenerative process, since elimination of the inflammatory induction could lessen neuronal damage

with the production of inflammatory factors and loss of dopaminergic neurons. In contrast, hippocampal or cortical cultures remained insensitive to LPS treatment at that concentration. Other intranigral inductors of inflammatory process, as histamine or thrombin, also induce the degeneration of the nigrostriatal dopaminergic system Dopaminergic degeneration in PD is specific for the nigrostriatal system. This specificity is well explained for some animal models of PD using toxins such as 6-OHDA or MPTP, since both MPPþ and 6-OHDA compete with DA for the DA uptake system (Decker et al., 1993). As have been pointed out above, the region-specific differential susceptibility of neurons to LPS may be attributed to


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differences in the amount of microglia present in the brain areas and consequently in the levels of inflammation-related factors produced by these cells. Activated microglia produces a variety of proinflammatory and cytotoxic factors including cytokines (such as TNF-a, IL-1b and chemokines), NO, reactive oxygen intermediates, quinolinic acid and arachidonic acid metabolites among others (Czlonkowska et al., 2002). It is important to note that the density of glial cells expressing iNOS is markedly increased in the SN of parkinsonian patients (Qureshi et al., 1995). TNF-a is increased in PD and is induced by LPS (Mogi et al., 1994), its receptor TNF-RI is expressed by nigral dopaminergic neurons (Boka et al., 1994), and it seems to be more expressed in those neurons of parkinsonian SN (Mogi et al., 2000). These and other microglial factors could contribute significantly to dopaminergic degeneration (Liu et al., 2000; Gao et al., 2002). We have studied the effect of the intranigral injection of inflammatory cytokines (TNF-a, IL-1b and IFN-g) on dopaminergic neurons viability, finding no significant changes with respect to controls (Casta~ no et al., 2002). Le et al. (2001) showed that even though microglial activation results in the release of several cytokines and reactive oxygen species, only NO and H2O2 appeared to mediate the microglia-induced dopaminergic cell injury. Physical trauma and PD are related (Lees, 1997; Taylor et al., 1999). Traumatic brain injury increases the permeability of blood-brain barrier and induces brain edema (Esen et al., 2003). Histamine is one of the few CNS neurotransmitters found to cause consistent blood-brain barrier opening (Abbott, 2000). We have evaluated the effects of a direct infusion of histamine in SN, striatum, medial septum and medial lemniscus. It produced a selective damage on dopaminergic neurons of SN along with the activation of microglia and a loss of glial fibrilary acidic protein-inmunolabeled astrocytes. However, transcription of GAD mRNA in SN was not altered. The pattern of choline acetyltransferase mRNA expressing cells and the pattern of serotonin immunolabeled cells in septum and in medial lemniscus respectively were not affected by histamine injection in these areas. We suggested that histamine-derived neurotoxicity, inflammatory process or increased blood-brain-barrier permeability, induced the degeneration of dopaminergic neurons along with the activation of microglia specifically in SN (Vizuete et al., 2000). We have also described that thrombin injection into nigrostriatal pathway induces the degeneration of nigral dopaminergic neurons along with the activation of microglia (Carre~ no-M€ uller et al., 2003). Thrombin is a multifunctional serine protease best known for its role in the blood coagulation cascade; it can induce a wide spectrum of responses as activation of cultured rodent microglia (M€ oller et al., 2000). When thrombin was injected into SN, a strong macrophage=microglia reaction was observed along with the induction of iNOS, IL-1a, IL-1b and TNF-a. In addition, the selective damage of dopaminergic neurons was also produced, evidenced by loss of TH immunostaining and TH-mRNA expressing cell bodies. However, thrombin did not affect the transcription of GAD mRNA neither in the SN nor in the striatum. These thrombin effects are produced by its biological activity since they almost disappeared when thrombin was heat-inactivated or injected along with its inhibitor a-(2-Naphthalenesulfonylglycyl)- 4-amidinoDL-phenylalaninepiperidide (a-NAPAP; Carre~ no-M€ uller et al., 2003). Thrombin

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is rapidly produced from prothrombin at the site of tissue injury, and also upon breakdown of the blood-brain barrier, which strongly suggests it could easily enter into the CNS. High concentrations of thrombin, such as those produced by a cerebral hemorrhage, appear to cause brain damage (Lee et al., 1995, 1996) and may also contribute to damage in Alzheimer’s disease and vascular dementia (Akiyama et al., 1992; Kario et al., 1999). Moreover, vascular parkinsonism has been described (Ondo et al., 2002). Antiinflammatory compounds inhibit the inflammatory process and the degeneration of the nigrostriatal dopaminergic system The implication of the inflammatory process in the degeneration of dopaminergic neurons has been further studied using different approaches. One of them is the protective effect of anti-inflammatory drugs against dopaminergic degeneration induced by proinflammatory compounds as LPS, which has been extensively reported. Casta~ no et al. (2002) showed the effect produced by dexamethasone, a potent anti-inflammatory drug, on the dopaminergic degeneration induced by LPS in SN. Dexamethasone inhibits not only OX-42-positive cells, but also the number of microglia=macrophages expressing MHC class II antigens induced by LPS. These observations are in good agreement with the well-known anti-inflammatory properties of dexamethasone, and also with previous works reporting that glucocorticoids down regulate MHC class II (Loughlin et al., 1993). Dexamethasone treatment has also been shown to prevent the loss of catecholamine content, TH activity and TH immunostaining induced by LPS injection (Casta~ no et al., 2002). All these data support the idea that degeneration of nigral dopaminergic neurons induced by LPS is produced by the inflammatory process induced by the inflammogen. Acknowledgements This work was supported by grants from Spanish Ministerio de Ciencia y Tecnologıá BFI 20013600 and SAF 2002-0195.

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