Recent Patents on CNS Drug Discovery, 2007, 2, 125-129
125
The Gastrin-Releasing Peptide Receptor as a Therapeutic Target in Central Nervous System Disorders Rafael Roesler1,2,*, Flávio Kapczinski3, João Quevedo4 , Felipe Dal Pizzol5 and Gilberto Schwartsmann2,6 1
Cellular and Molecular Neuropharmacology Research Group, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90046-900 Porto Alegre, RS, Brazil, 2Cancer Research Laboratory, Academic Hospital Research Center, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil, 3Laboratory of Experimental Psychiatry and Bipolar Disorders Program, Academic Hospital Research Center, Federal University of Rio Grande do Sul, 90035003 Porto Alegre, RS, Brazil, 4Laboratory of Neurosciences and Department of Medicine, University of Southern Santa Catarina, 88806-000 Criciúma, SC, Brazil, 5Laboratory of Experimental Physiopathology and Department of Medicine, University of Southern Santa Catarina, 88806-000 Criciúma, SC, Brazil, 6Department of Internal Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil Received: May 2, 2007; Accepted: May 7, 2007; Revised: May 9, 2007 Abstract: Gastrin-releasing peptide (GRP) is a mammalian counterpart of the amphibian peptide bombesin (BB) that stimulates cell proliferation, acts as a growth factor in the pathogenesis of many types of cancer, and regulates several aspects of neuroendocrine function. BB and GRP act by binding to the GRP-preferring type of BB receptor (GRPR, also known as BB2 receptor), a member of the superfamily of G-protein coupled membrane receptors. This review summarizes recent evidence from animal and human studies indicating that abnormalities in GRPR function in the brain might play a role in the pathogenesis of neurological and psychiatric disorders, and suggesting that BB, GRP, and GRPR antagonists might display therapeutic actions in central nervous system diseases. Recent patent applications on GRPR-related methods for treating brain disorders are introduced.
Keywords: Bombesin-like peptides, gastrin-releasing peptide, gastrin-releasing peptide receptor, neuropeptides, neurological disorders. BOMBESIN-LIKE PEPTIDES AND THEIR RECEPTORS IN THE CENTRAL NERVOUS SYSTEM Bombesin (BB) is a 14 amino acid peptide initially isolated from the skin of frog Bombina bombina. It was later described that gastrin-releasing peptide (GRP), a 27 amino acid peptide functionally and structurally related to BB, is a mammalian counterpart of BB (Table 1). BB and GRP, as well as other related peptides such as neuromedin B (NMB), constitute a family of BB-like peptides (BLPs). BLPs affect a range of cellular and neuroendocrine functions, including cell proliferation and differentiation, cancer growth, feeding behavior, and stress responses (for recent reviews, see [1 - 4]). Table 1. Structures of Bombesin (BB) and Gastrin-Releasing Peptide (GRP) Bombesin: Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 Gastrin-releasing peptide: Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys-Met-Tyr-ProArg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 Reproduced from [4].
Early studies investigating the presence of BB binding sites in the mammalian central nervous system (CNS) showed that BB bound with high affinity to rat brain membranes. The hippocampus, a brain area critically involved in mediating cognitive function as well as in the pathogenesis of several neurodegenerative and neuropsychiatric disorders, had the highest density of specific BB binding sites [5]. Subsequent studies identified the occurrence of *Address correspondence to this author at the Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Centro, 90046-900 Porto Alegre, RS, Brazil; Tel: +55 51 3308 3183; Fax: +55 51 3308 3121; E-mail:
[email protected] 1574-8898/07 $100.00+.00
endogenous BLPs as neuropeptides in the rat CNS. It has been proposed that GRP, the main mammalian BLP, might act as a cotransmitter released from both central and peripheral excitatory neurons, regulating aspects of brain function including memory and emotional processing [1, 4, 6 - 8]. THE GASTRIN-RELEASING PEPTIDE RECEPTOR (GRPR) AND ASSOCIATED SIGNAL TRANSDUCTION PATHWAYS IN THE CNS The biological actions of BB and GRP are at least partially mediated by their binding to the GRP-preferring type of BB receptor (GRPR, also known as BB2 receptor). GRPR is a member of the G-protein coupled receptor superfamily containing seven transmembrane domains and 384 amino acids [9 - 11] (Table 2). GRPR is highly expressed in the brain. Studies using in vitro autoradiographic techniques indicated that brain areas containing Table 2. Molecular Structure of the Gastrin-Releasing Peptide Receptor (GRPR) (1–60) MALNDCFLLN LEVDHFMHCN ISSHSADLPV NDDWSHPGIL YVIPAVYGVI ILIGLIGNIT (61–120) LIKIFCTVKS MRNVPNLFIS SLALGDLLLL ITCAPVDASR YLADRWLFGR IGCKLIPFIQ (121–180) LTSVGVSVFT LTALSADRYK AIVRPMDIQA SHALMKICLK AAFIWIISML LAIPEAVFSD (181–240) LHPFHEESTN QTFISCAPYP HSNELHPKIH SMASFLVFYV IPLSIISVYY YFIAKNLIQS (241–300) AYNLPVEGNI HVKKQIESRK RLAKTVLVFV GLFAFCWLPN HVIYLYRSYH YSEVDTSMLH (301–360) FVTSICARLL AFTNSCVNPF ALYLLSKSFR KQFNTQLLCC QPGLIIRSHS TGRSTTCMTS (361–384) LKSTNPSVAT FSLINGNICH ERYV The locations of each of the seven predicted transmembrane domains are underlined. Reproduced from [4].
© 2007 Bentham Science Publishers Ltd.
126 Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 2
Roesler et al.
high densities of GRPRs include the olfactory bulb, nucleus accumbens, caudate putamen, central amygdala, dorsal hippocampal formation, as well as the paraventricular, central medial, and paracentral thalamic nuclei [1, 4, 12, 13]. A recent seminal immunohistochemical study using affinity-purified GRPR antibodies to examine the precise distribution of GRPR in the mouse brain has shown that GRPR immunoreactivity was widely distributed in the neuronal dendrites and cell bodies of the isocortex, hippocampus, piriform cortex, amygdala, hypothalamus, and brain stem, with high concentrations in the dorsal hippocampus and lateral amygdala [14]. Studies using cancer and neuroendocrine cell lines have shown that intracellular responses to GRPR activation involve the protein kinase C (PKC) and mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated protein kinase (ERK) signaling pathways [15 - 17]. In the brain, GRP-induced neuronal membrane depolarization in the rat hippocampus is blocked by a phospholipase C (PLC) inhibitor [18], and studies in our laboratory have recently indicated that GRPR regulation of neuronal function in the rat hippocampus depends on the PKC, MAPK and protein kinase A (PKA) pathways [7]. An increasing body of evidence indicates that BLPs and the GRPR might play a role in the pathogenesis of CNS diseases (reviewed in [4]). Below we review current evidence supporting the view that the GRPR should be considered a novel therapeutic target for the treatment of neurological and psychiatric disorders and introduce recent patent applications that have emerged from this evidence. ABNORMALITIES DISORDERS
IN
GRPR
SIGNALING
IN
CNS
Evidence from Human Studies Although a causative role of GRPR dysfunction in brain disorders has not been established, alterations in the levels of BBlike peptides or GRPR function in patients with neurodegenerative, neuropsychiatric, and neurodevelopmental disorders have been reported. For instance, the concentration of BLPs was significantly reduced in the caudate nucleus and globus pallidus of patients with Parkinson’s disease [19], as well as in the urine and cerebrospinal fluid (CSF) of patients with schizophrenia [20, 21]. Alterations in GRP levels in the human CNS have also been proposed to be involved in anorexia, bulimia nervosa, and mood disorders [22, 23]. Alzheimer’s disease (AD) and brain aging might involve a dysfunction of cellular calcium signaling in neurons. Increasing evidence from animal and human studies has indicated that abnormalities in BLP-induced, GRPR-mediated cellular signaling might be associated with AD. BB stimulates calcium release from BB-releasable calcium stores in the endoplasmic reticulum (ER) through GRPR activation. It has been shown that calcium signals in fibroblasts from familial and non-familial AD cases can be either enhanced or decreased when compared to controls [24 - 28]. For instance, in fibroblasts from patients with familial Alzheimer’s disease presenting the Swedish APP670/671 mutation, BB-induced elevations in calcium were significantly reduced [25]. Abnormalities in BB-regulated calcium homeostasis observed in AD fibroblasts have been proposed to involve alterations in oxidative stress [24 - 27, 29]. In addition, fibroblasts from patients with AD might have a reduced number of BB receptors [28]. These findings suggest that alterations in GRPR number and BLP-triggered signaling might play a role in the dysregulation of calcium homeostasis and oxidative stress associated with neurodegeneration and cognitive dysfunction in AD patients. Alterations in GRPR function might also be involved in the pathogenesis of neurodevelopmental disorders. GRPR has emerged as a candidate gene for infantile autism [30, 31]. An X;8 translocation occurring in the first intron of the GRPR gene has
been identified in a female patient with multiple exostoses and autism accompanied by mental retardation and epilepsy [31]. Table 3 summarizes the main findings indicating possible alterations in BB-like peptide levels and GRPR function in patients with brain disorders. Table 3. Abnormalities in the Levels of Bombesin-Like Peptides (BLPs) and the Gastrin-Releasing Peptide Receptor (GRPR) Pathway in Patients with Central Nervous System (CNS) Disorders CNS disorder
Findings
References
Schizophrenia
Reduced levels of BB-like peptides in urine and CSF
[20, 21]
Parkinson’s disease
Reduced levels of BB-like peptides in caudate nucleus and globus pallidus
[19]
Alzheimer’s disease
Enhanced BB-induced calcium release in fibroblasts
[28]
Alzheimer’s disease
Reduced number of BB binding sites
[28]
Alzheimer’s disease presenting the Swedish APP670/671 mutation
Reduced BB-induced calcium mobilization in fibrobasts
[25]
Autism
X;8 translocation in GRPR gene
[31]
Adapted from [4].
Evidence from Genetic Mouse Models GRPR-deficient knockout mice have been developed and some of their behavioral and neurophysiological responses relevant for CNS disorders have been examined [8, 32 - 34]. GRPR-deficient mice showed increased locomotor activity and non-aggressive social behaviors [32 - 34]. In addition, mice lacking GRPRs show enhanced fear memory and amygdalar synaptic plasticity, supporting the view that GRPRs in the amygdala are importantly involved in regulating learned fear and anxiety [8]. Together, these findings suggest that GRPR is involved in mediating and/or regulating aspects of behavior relevant for brain disorders (e.g., social behavior, cognition, fear, anxiety, and formation of traumatic memories). Studies using other genetic mouse models have supported the view that GRPR signaling might be altered in CNS disease. Because mutations in the presenilin-1 (PS-1) gene on chromosome 14 are causally linked to many cases of early-onset inherited AD, transgenic mice bearing a mutation in the PS-1 gene have been developed as an animal model of AD [35, 36]. In fibroblasts and neurons of these genetically modified mice, enhanced BB-induced intracellular calcium release has been demonstrated compared to controls [35]. Importantly, the alterations in BB-induced enhancement of calcium signaling observed in this mouse model resembles those described in patients with AD described above. POTENTIAL THERAPEUTIC EFFECTS OF DRUGS ACTING AT THE GRPR IN CNS DISORDERS: EVIDENCE FROM ANIMAL MODELS Rodent models have been used to investigate the effects of drugs acting at the GRPR in several aspects of brain function. Intracerebral infusions of BB induce grooming behavior mediated
GRPR as a Target in CNS Disorders
by GRPR activation in rats, an effect that might be related to stress responses [1, 37 - 40]. BB administration induces other autonomic, endocrine and behavioral effects similar to those elicited by exposure to stressors, suggesting a possible role of GRPRs in mediating stress and anxiety responses [1, 41]. BB administration also suppresses food intake in rats [42], mice [43], and humans [44]. The BB-induced reduction in food intake is attenuated by systemic administration of BB receptor antagonists [45], whereas, conversely, intracerebral infusion of a selective GRPR antagonist enhances milk intake [46]. The role of the GRPR in regulating food intake is consistent with the view that dysfunction of this system might contribute to psychiatric disorders such as anorexia nervosa, bulimia, and depression [1, 22, 23, 47]. BLPs and other drugs acting at the GRPR regulate cognitive function and emotional memory. Early pharmacological studies have shown that systemic or intracerebral administration of BB or GRP enhances memory storage in mice and rats [48, 49]. More recently, a series of studies from our laboratory has examined the effects of GRPR agonists and antagonists on learning and memory in naive rodents as well as in experimental models of CNS disorders. Our results have indicated that memory formation can be modulated by either systemic or intracerebral administration of drugs acting at the GRPR. Thus, GRPR activation in the dorsal hippocampus by BB intrahippocampal microinfusion produces a consistent enhancement of fear-motivated memory in rats. Importantly, BB at an otherwise ineffective dose prevented memory impairment in a rat model of dementia associated with AD [7] (Fig. 1). These findings strongly suggest that GRPR agonists such as BB and GRP could be evaluated as potential cognitive-enhancing drugs. Conversely, GRPR blockade by systemic administration of the GRPR selective antagonist [D-Tpi6, Leu13 psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095), or microinfusion of RC-3095 into the dorsal hippocampus or the basolateral nucleus of the amygdala impaired retention of fear-motivated conditioning [6, 50, 51], although RC-3095 at a higher dose induced a memory-enhancing effect mimicking that of BB when infused into the hippocampus [52]. In addition, intrahippocampal administration of RC-3095
Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 2
127
blocked extinction of fear memory in rats, an experimental model relevant for post-traumatic stress disorder (PTSD) [53], and systemic administration of RC-3095 alters anxiety-related behavior assessed in the elevated plus maze in rats [54]. The view that the BLPs and the GRPR regulate fear memory and anxiety is further supported by the finding that systemic administration of GRPR antagonists impair aversively-motivated memory in mice [55], as well as by recent evidence that infusion of GRP or a GRPR antagonist affect expression of fear conditioning in rats [56]. Furthermore, these pharmacological findings are consistent with the genetic studies showing altered fear memory in GRPR-deficient mice reviewed above [8]. The modulatory actions of the GRPR on memory formation depends on the MAPK, PKC, and PKA signaling pathways [7] and might involve functional interactions with other neurotransmitter and receptor systems [52, 57] and neurotrophins [58]. Together, these findings provide a strong body of evidence indicating that the GRPR is importantly involved in regulating memory formation for fearful events. This might have therapeutic implications for the development of GRPR agonists and antagonists as cognitive enhancers in patients with neurodegenerative disorders involving memory dysfunction, such as AD, or psychiatric disorders related to fear and traumatic memories, such as PTSD and other anxiety disorders [4, 59]. Other experiments from our laboratory have provided further support for the view that the GRPR might be involved in schizophrenia and autism, and drugs acting at the GRPR could be tested as potential therapeutic agents in psychiatric disorders. Thus, rats given GRPR blockade during CNS development by neonatal administration of RC-3095 showed pronounced deficits in social behavior and cognitive function consistent with features of models of autism and schizophrenia [60]. Moreover, systemic administration of RC-3095 attenuated stereotyped behaviors induced by the dopamine receptor agonist apomorphine in mice [61]. Stereotyped behaviors are features of psychiatric disorders such as schizophrenia, obsessive-compulsive disorder and autism, and apomorphine-induced stereotypy has been considered an animal model of psychosis. This finding provided preliminary evidence suggesting that GRPR antagonists might display antipsychotic activity. RECENT PATENTS ON GRPR-BASED STRATEGIES FOR THE TREATMENT OF CNS DISORDERS Recent patent applications have emerged from preclinical evidence of the role of GRPR in CNS disorders (Table 4). Based on the finding that GRPR-deficient mice show enhanced fear memory [8], WO05060625A2 applies a method for treating or preventing fear-related psychiatric disorders with GRPR agonists [67]. The authors of the present review article are inventors of US2006 0160744A1 [68] and WO06063837A2 [69], which apply the use of GRPR antagonists to treat patients with brain disorders, preferably bipolar disorder. That claim was supported by the finding by Quevedo and colleagues that systemic administration of RC-3095 blocked amphetamine-induced hyperlocomotion in rats, an animal model of mania [68, 69].
Fig. (1). The gastrin-releasing peptide receptor (GRPR) agonist bombesin (BB) prevents memory impairment in a rat model of cognitive dysfunction associated with Alzheimer’s disease (AD). Adult male rats were given a bilateral 0.5 μl-infusion of BB (0.002 μg) or saline (SAL) into the dorsal hippocampus 10 min before training in step-down inhibitory avoidance (IA), a type of fear-motivated conditioning. Immediately after training, rats were given a bilateral intrahippocampal 0.5 μl-infusion of the neurotoxic fragment of the Alzheimer peptide, beta-amyloid peptide (Abeta) (25-35) (0.02 μg), or distilled water (DW). Data are mean + SEM 24-h retention step-down latency (s), used as a measure of fear memory retention. Infusion of Abeta (25-35) produced memory impairment in rats pretreated with SAL but not in animals pretreated with BB. Reproduced from [7], with permission.
CURRENT & FUTURE DEVELOPMENTS Although the potential of the GRPR as a therapeutic target in cancer has been proposed for many years, only more recently it emerged as promising a target in psychiatric and neurological disorders. The evidence from animal studies reviewed above indicates that GRPR agonists and antagonists could display beneficial effects in a range of neurological and psychiatric disorders, having potential beneficial effects as cognitive enhancers, antipsychotics, anxiolytics or anti-manic agents. The possibility that drugs acting at the GRPR have also neuroprotective activities in the CNS in stroke, neurotrauma, or neurodegenerative disorders remains to be investigated, although recent evidence indicates that BB might induce neuroprotective effects in peripheral ganglia [70, 71].
128 Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 2
Table 4.
Roesler et al.
Recent Patents on Gastrin-Releasing Peptide Receptor (GRPR)-Based Strategies for Treating Brain Disorders
Patent number
Title
Publication date
Reference
WO05060625A2
GRP receptor-related methods for treating and preventing fear-related disorders
2005-07-07
[67]
US20060160744A1
Use of bombesin/gastrin-releasing peptide antagonists for the treatment of inflammatory conditions, acute lung injury and bipolar disorder
2006-07-20
[68]
WO06063837A2
Use of bombesin/gastrin-releasing peptide antagonists for the treatment of inflammatory conditions, acute lung injury and bipolar disorder
2006-06-22
[69]
One crucial issue regarding the clinical usefulness of drugs acting at the GRPR is to consider whether available GRPR ligands are clinically tolerable in human subjects. Previous clinical studies in the fields of gastroenterology and oncology have indicated that GRPR agonists (BB or GRP), GRPR antagonists (RC-3095 and BIM26226), and antibodies against BLPs can be administered intravenously in humans without inducing overt toxicity [44, 62 66]. Thus, at least some GRPR agonists and antagonists could be safely administered to human subjects, and clinical trials evaluating the effects of these agents in patients with CNS disorders are warranted. A limitation for the clinical use of BB, GRP, and synthetic BB analogs such as RC-3095 in patients with CNS disorders is the intravenous route of administration. Thus, one of the challenges in this field is the development of orally active, small molecule GRPR agonists and antagonists. Overall, current evidence indicates that GRPR-based therapeutic strategies may be useful for the treatment of neurological and psychiatric disorders. ACKNOWLEDGEMENTS Research in our laboratories reviewed in the present article (references [4, 6, 7, 50 - 54, 57 - 61, 66] has been supported by grants from CNPq, the South American Office for Anticancer Drug Development, and Zentaris GmbH (Frankfurt, Germany). Experiments described in patent applications US20060160744A1 and WO2006063837A2 and reviewed in the present article (references [68 and 69]) were supported by the South American Office for Anticancer Drug Development and Zentaris GmbH and carried out at the University of Southern Santa Catarina (UNESC, Criciúma, Brazil). REFERENCES [1]
[2] [3] [4]
[5] [6]
[7]
[8]
[9]
[10]
[11]
Moody TW, Merali Z. Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications. Peptides 2004; 25: 511-20. Ohki-Hamazaki H, Iwabuchi M, Maekawa F. Development and function of bombesin-like peptides and their receptors. Int J Dev Biol 2005; 49: 293-300. Patel O, Shulkes A, Baldwin GS. Gastrin-releasing peptide and cancer. Biochim Biophys Acta 2006; 1766: 23-41. Roesler R, Henriques JAP, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets 2006; 5: 197-204. Moody TW, Pert CB, Rivier J, Brown MR. Bombesin: specific binding to rat brain membranes. Proc Natl Acad Sci USA 1978; 75: 5372-76. Roesler R, Lessa D, Venturella R, et al. Bombesin/gastrin-releasing peptide receptors in the basolateral amygdala regulate memory consolidation. Eur J Neurosci 2004; 19: 1041-45. Roesler R, Luft T, Oliveira SH, et al. Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus. Neuropharmacology 2006; 51: 350-57. Shumyatsky GP, Tsvetkov E, Malleret G, et al. Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 2002; 111: 905-18. Battey J, Wada E, Corjay M, et al. Molecular genetic analysis of two distinct receptors for mammalian bombesin-like peptides. J Natl Cancer Inst Monogr 1992; 13: 141-44. Battey JF, Way JM, Corjay MH, et al. Molecular cloning of the bombesin/ gastrin-releasing peptide receptor from Swiss 3T3 cells. Proc Natl Acad Sci USA 1991; 88: 395-99. Spindel ER, Giladi E, Brehm P, Goodman RH, Segerson TP. Cloning and functional characterization of a complementary DNA encoding the murine
[12] [13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] [23]
[24] [25]
[26]
[27]
[28]
[29]
[30]
[31] [32]
[33]
[34]
fibroblast bombesin/gastrin-releasing peptide receptor. Mol Endocrinol 1990; 4: 1956-63. Wolf SS, Moody TW. Receptors for GRP/bombesin-like peptides in the rat forebrain. Peptides 1985; 6 Suppl 1: 111-14. Wolf SS, Moody TW, O'Donohue TL, Zarbin MA, Kuhar MJ. Autoradiographic visualization of rat brain binding sites for bombesin-like peptides. Eur J Pharmacol 1983; 87: 163-64. Kamichi S, Wada E, Aoki S, Sekiguchi M, Kimura I, Wada K. Immunohistochemical localization of gastrin-releasing peptide receptor in the mouse brain. Brain Res 2005; 1032: 162-70. Hellmich MR, Ives KL, Udupi V, et al. Multiple protein kinase pathways are involved in gastrin-releasing peptide receptor-regulated secretion. J Biol Chem 1999; 274: 23901-909. Kim HJ, Evers BM, Litvak DA, Hellmich MR, Townsend CM Jr. Signaling mechanisms regulating bombesin-mediated AP-1 gene induction in the human gastric cancer SIIA. Am J Physiol Cell Physiol 2000; 279: C326-34. Xiao D, Qu X, Weber HC. Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. Cell Signal 2003; 15: 945-53. Lee K, Dixon AK, Gonzalez I, et al. Bombesin-like peptides depolarize rat hippocampal interneurones through interaction with subtype 2 bombesin receptors. J Physiol 1999; 518: 791-802. Bissette G, Nemeroff CB, Decker MW, Kizer JS, Agid Y, Javiy-Agid F. Alterations in regional brain concentrations of neurotensin and bombesin in Parkinson's disease. Ann Neurol 1985; 17: 324-28. Gerner RH, van Kammen DP, Ninan PT. Cerebrospinal fluid cholecystokinin, bombesin and somatostatin in schizophrenia and normals. Prog Neuropsychopharmacol Biol Psychiatry 1985; 9: 73-82. Olincy A, Leonard S, Young DA, Sullivan B, Freedman R. Decreased bombesin peptide response to cigarette smoking in schizophrenia. Neuropsychopharmacology 1999; 20: 52-59. Merali Z, McIntosh J, Anisman H. Role of bombesin-related peptides in the control of food intake. Neuropeptides 1999; 33: 376-86. Frank GK, Kaye WH, Ladenheim EE, McConaha C. Reduced gastrin releasing peptide in cerebrospinal fluid after recovery from bulimia nervosa. Appetite 2001 37: 9-14. Gibson GE, Huang HM. Oxidative stress in Alzheimer's disease. Neurobiol Aging 2005; 26: 575-78. Gibson GE, Vestling M, Zhang H, et al. Abnormalities in Alzheimer's disease fibroblasts bearing the APP670/671 mutation. Neurobiol Aging 1997; 18: 573-80. Gibson GE, Zhang H, Toral-Barza L, Szolosi S, Tofel-Grehl B. Calcium stores in cultured fibroblasts and their changes with Alzheimer's disease. Biochim Biophys Acta 1996; 1316: 71-77. Huang HM, Chen HL, Xu H, Gibson GE. Modification of endoplasmic reticulum Ca2+ stores by select oxidants produces changes reminiscent of those in cells from patients with Alzheimer disease. Free Radic Biol Med 2005; 39: 979-989. Ito E, Oka K, Etcheberrigaray R, et al. Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc Natl Acad Sci USA 1994; 91: 534-538. Huang HM, Zhang H, Ou HC, Chen HL, Gibson GE. alpha-keto-betamethyl-n-valeric acid diminishes reactive oxygen species and alters endoplasmic reticulum Ca(2+) stores. Free Radic Biol Med 2004; 37: 17791789. Ishikawa-Brush Y, Powell JF, et al. Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene. Hum Mol Genet 1997; 6: 1241-1250. Marui T, Hashimoto O, Nanba E, et al. Gastrin-releasing peptide receptor (GRPR) locus in Japanese subjects with autism. Brain Dev 2004; 26: 5-7. Wada E, Watase K, Yamada K, et al. Generation and characterization of mice lacking gastrin-releasing peptide receptor. Biochem. Biophys. Res. Commun 1997; 239: 28-33. Yamada K, Wada E, Wada K. Male mice lacking the gastrin-releasing peptide receptor (GRP-R) display elevated preference for conspecific odors and increased social investigatory behaviors. Brain Res 2000; 870: 20-26. Yamada K, Wada E, Wada K. Female gastrin-releasing peptide receptor (GRP-R)-deficient mice exhibit altered social preference for male
GRPR as a Target in CNS Disorders
[35]
[36]
[37] [38]
[39] [40]
[41]
[42] [43] [44] [45]
[46] [47] [48] [49]
[50]
[51]
[52]
[53]
conspecifics: implications for GRP/GRP-R modulation of GABAergic function. Brain Res 2001; 894: 281-287. Leissring MA, Akbari Y, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 2000; 149: 793-798. Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin M, Mattson MP. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 1999; 5: 101-106. Gmerek DE, Cowan A. Studies on bombesin-induced grooming in rats. Peptides 1983; 4: 907-913. Johnston SA, Merali Z. Specific neuroanatomical and neurochemical correlates of locomotor and grooming effects of bombesin. Peptides 1988; 9 Suppl 1: 245-256. Kulkosky PJ, Gibbs J, Smith GP. Behavioral effects of bombesin administration in rats. Physiol Behav 1982; 28: 505-12. Piggins H, Merali Z. The effects of concurrent D-1 and D-2 dopamine receptor blockade with SCH 23390 and eticlopride, on bombesin-induced behaviours. Prog Neuropsychopharmacol Biol Psychiatry 1989; 13: 583-94. Merali Z, Kent P, Anisman H. Role of bombesin-related peptides in the mediation or integration of the stress response. Cell Mol Life Sci 2002; 59: 272-87. Gibbs J, Fauser DJ, Rowe EA, Rolls BJ, Rolls ET, Maddison SP. Bombesin suppresses feeding in rats. Nature 1979; 282: 208-10. Taylor IL, Garcia R. Effects of pancreatic polypeptide, caerulein, and bombesin on satiety in obese mice. Am J Physiol 1985; 248: G277-80. Muurahainen NE, Kissileff HR, Pi-Sunyer FX. Intravenous infusion of bombesin reduces food intake in humans. Am J Physiol 1993; 264: R350-4. Flynn FW. Bombesin receptor antagonists block the effects of exogenous bombesin but not of nutrients on food intake. Physiol Behav 1997; 62: 79198. Flynn FW. Fourth ventricular injection of selective bombesin receptor antagonists facilitates feeding in rats. Am J Physiol 1993; 264: R218-21. Flynn FW. Bombesin-like peptides in the regulation of ingestive behavior. Ann N Y Acad Sci 1994; 739: 120-34. Flood JF, Morley JE. Effects of bombesin and gastrin-releasing peptide on memory processing. Brain Res 1988; 460: 314-22. Williams CL, McGaugh JL. Enhancement of memory processing in an inhibitory avoidance and radial maze task by post-training infusion of bombesin into the nucleus tractus solitarius. Brain Res 1994; 654: 251-56. Roesler R, Meller CA, Kopschina MI, Souza DO, Henriques JA, Schwartsmann G. Intrahippocampal infusion of the bombesin/gastrinreleasing peptide antagonist RC-3095 impairs inhibitory avoidance retention. Peptides 2003; 24: 1069-74. Roesler R, Kopschina MI, Rosa RM, Henriques JA, Souza DO, Schwartsmann G. RC-3095, a bombesin/gastrin-releasing peptide antagonist, impairs aversive but not recognition memory in rats. Eur J Pharmacol 2004; 486: 35-41. Dantas AS, Luft T, Henriques JA, Schwartsmann G, Roesler R. Opposite effects of low and high doses of the gastrin-releasing peptide receptor antagonist RC-3095 on memory consolidation in the hippocampus: possible involvement of the GABAergic system. Peptides 2006; 27: 2307-12. Luft T, Flores DG, Vianna MR, Schwartsmann G, Roesler R, Izquierdo I. A role for hippocampal gastrin-releasing peptide receptors in extinction of aversive memory. Neuroreport 2006; 17: 935-39.
Recent Patents on CNS Drug Discovery, 2007, Vol. 2, No. 2 [54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62] [63]
[64]
[65]
[66]
[67] [68] [69] [70]
[71]
129
Martins MR, Reinke A, Valvassori SS, et al. Non-associative learning and anxiety in rats treated with a single systemic administration of the gastrinreleasing peptide receptor antagonist RC-3095. Peptides 2005; 26: 2525-29. Santo-Yamada Y, Yamada K, Wada E, Goto Y, Wada K. Blockade of bombesin-like peptide receptors impairs inhibitory avoidance learning in mice. Neurosci Lett 2003; 340: 65-68. Mountney C, Sillberg V, Kent P, Anisman H, Merali Z. The role of gastrinreleasing peptide on conditioned fear: differential cortical and amygdaloid responses in the rat. Psychopharmacology 2006; 189: 287-296. Venturella R, Lessa D, Luft T, Roozendaal B, Schwartsmann G, Roesler R. Dexamethasone reverses the memory impairment induced by antagonism of hippocampal gastrin-releasing peptide receptors. Peptides 2005; 26: 821-55. Preissler T, Luft T, Kapczinski F, Quevedo, J, Schwartsmann G, Roesler R. Basic fibroblast growth factor prevents the memory impairment induced by gastrin-releasing peptide receptor antagonism in area CA1 of the rat hippocampus. Neurochem Res 2007; DOI: 10.1007/s11064-007-9320-2. Roesler R, Henriques JA, Schwartsmann G. Neuropeptides and anxiety disorders: bombesin receptors as novel therapeutic targets. Trends Pharmacol Sci 2004; 25: 241-42. Presti-Torres J, de Lima MN, Scalco FS, et al. Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders. Neuropharmacology 2007; 52: 724-32. Meller CA, Henriques JA, Schwartsmann G, Roesler R. The bombesin/ gastrin releasing peptide receptor antagonist RC-3095 blocks apomorphine but not MK-801-induced stereotypy in mice. Peptides 2004; 25: 585-88. Clive S, Jodrell D, Webb D. Gastrin-releasing peptide is a potent vasodilator in humans. Clin Pharmacol Ther 2001; 69: 252-59. Gutzwiller P, Drewe J, Hildebrand P, Rossi L, Lauper JZ, Beglinger C. Effect of intravenous human gastrin-releasing peptide on food intake in humans. Gastroenterology 1994; 106: 1168-73. Hildebrand P, Lehmann FS, Ketterer S, et al. Regulation of gastric function by endogenous gastrin releasing peptide in humans: studies with a specific gastrin releasing peptide receptor antagonist. Gut 2001; 49: 23-28. Mulshine JL, Avis I, Treston AM, et al. Clinical use of a monoclonal antibody to bombesin-like peptide in patients with lung cancer. Ann N Y Acad Sci 1988; 547: 360-72. Schwartsmann G, DiLeone LP, Horowitz M, et al. A phase I trial of the bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC3095 in patients with advanced solid malignancies. Invest New Drugs 2006; 24: 403-12. Kandel, E.R., Shumyatsky, G., Bolshakov, V., Malleret, G.: WO05060625A2 (2005). Schwartsmann, G., Roesler, R., Dal Pizzol, F., Quevedo, J., Kapczinski, F.: US20060160744A1 (2006). Schwartsmann, G., Roesler, R., Dal Pizzol, F., Quevedo, J., Kapczinski, F.: WO06063837A2 (2006). Higuchi K, Kimura O, Furukawa T, Kinoshita H, Iwai N. Bombesin can rescue the enteric ganglia from FK506 neurotoxicity on small bowel transplantation. J Pediatr Surg 2006; 41: 1957-61. Roesler R, Schwartsmann G, Dal Pizzol F. Bombesin protection against FK506 neurotoxicity. J Pediatr Surg 2007; 42: 750.
