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Purpose: Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists., Methods: D283 MB cells were treated with different doses of the HDACi sodium butyrate (NaB), the neuromedin B receptor (NMBR) antagonist BIM-23127, the gastrin releasing peptide receptor (GRPR) antagonist RC-3095, or combinations of NaB with each receptor antagonist. Cell viability was examined by cell counting., Results: NaB alone or combined with receptor antagonists reduced cell viability at all doses tested. BIM-23127 alone did not affect cell viability, whereas RC-3095 at an intermediate dose significantly increased cell number., Conclusion: Although HDACi are promising agents to inhibit MB growth, the present results provide preliminary evidence that combining HDACi with bombesin receptor antagonists is not an effective strategy to improve the effects of HDACi against MB cells.

RC-3095, a selective GRPR antagonist, has been shown to have anti-inflammatory properties in different models of inflammation. However, its protective effect on lungs submitted to lung ischemia-reperfusion injury has not been addressed before. Then, we administrated RC-3095 intravenously before and after lung reperfusion using an animal model of lung ischemia-reperfusion injury (LIRI) by clamping the pulmonary hilum. Twenty Wistar rats were subjected to an experimental model in four groups: SHAM, ischemia-reperfusion (IR), RC-Pre, and RC-Post. The final mean arterial pressure significantly decreased in IR and RC-Pre compared to their values before reperfusion (P < 0.001). The RC-Post group showed significant decrease of partial pressure of arterial oxygen at the end of the observation when compared to baseline (P = 0.005). Caspase-9 activity was significantly higher in the RC-Post as compared to the other groups (P < 0.013). No significant differences were observed in eNOS activity among the groups. The groups RC-Pre and RC-Post did not show any significant decrease in IL-1β (P = 0.159) and TNF-α (P = 0.260), as compared to IR. The histological score showed no significant differences among the groups. In conclusion, RC-3095 does not demonstrate a protective effect in our LIRI model. Additionally, its use after reperfusion seems to potentiate cell damage, stimulating apoptosis.

Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors and is involved in signal transmission in both the central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. In recent years, studies have suggested the relationship of GRP and inflammatory diseases. RC-3095, a selective GRPR antagonist, was found to have antiinflammatory properties in models of arthritis, gastritis, uveitis and sepsis. Furthermore, GRP mediates air pollutioninduced airway hyperreactivity and airway inflammation in mice. In conclusion, GRP and its receptor are relevant to the inflammatory response, being a potential therapeutic target several diseases are related to inflammation.

The pathophysiology of gastritis involves an imbalance between gastric acid attack and mucosal defence. In addition, the gastric mucosal injury results in adenosine triphosphate (ATP) depletion leading to mitochondrial dysfunction. Several studies have shown the association of mitochondrial disorders with gastrointestinal dysfunction. In the present study, we investigated the activity of mitochondrial respiratory chain complexes activity in the stomach of rats with gastritis induced by indomethacin (IDM) and treated with omeprazole (OM), N-acetylcysteine (NAC) and the gastrin-releasing peptide receptor (GRPR) antagonist RC-3095. Adult male Wistar rats were pre-treated for 7 days with OM, NAC, RC-3095, combination of OM plus RC-3095, OM plus NAC and water (control). The animals were then submitted to fasting for 24 hr; IDM was administered. The rats were killed 6 hr later, and the stomachs were used for evaluation of macroscopic damage and respiratory chain activity. Our results showed that complex I and IV activities were not affected by administration of IDM. On the other hand, complex II and III activities were inhibited. In addition, OM plus RC-3095 and OM plus NAC did not reverse complex II activity inhibition. However, the complex III activity inhibition was reversed only with the combined use of OM plus RC-3095 and OM plus NAC. Our results are in agreement with previous studies indicating mitochondrial dysfunction in the pathophysiology of gastrointestinal tract disease and we suggest that GRPR antagonism might be a novel therapeutic strategy in gastritis., (© 2010 The Authors. Basic & Clinical Pharmacology & Toxicology © 2010 Nordic Pharmacological Society.)

Alterations in attachment behavior might play a role in the dysfunction in social behavior displayed by autistic infants. Here we show that neonatal gastrin-releasing peptide receptor (GRPR) blockade induces a reduction in maternal odor preference, a task involving attachment behavior, in infant rats. These findings provide the first evidence that the GRPR regulates odor preference, supporting the view that the GRPR is involved in attachment and social behaviors., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Objective: We report the effects of the gastrin-releasing peptide (GRP) receptor antagonist RC-3095 in an acute inflammation model induced by carrageenan., Methods: Male Wistar rats received saline or saline containing 2% lambda-carrageenan into the pleural cavity, with some also receiving RC-3095 3 mg/kg subcutaneously, immediately after surgery. Four hours later, the rats were killed and pleural exudate was obtained for evaluation of total cell count, lactate dehydrogenase activity, total protein, cytokines analysis and nitrite/nitrate concentrations; myeloperoxidase (MPO) activity and oxidative stress were evaluated in the lung., Results: RC-3095 exhibited pronounced anti-inflammatory actions by inhibition of leukocyte influx and blockade of MPO, nitrite/nitrate and cytokine levels. Moreover, the results showed that RC-3095 elicits action against oxidative damage in lipids and proteins, as well as increasing cell viability., Conclusion: The present findings suggest that GRP plays a role in acute inflammation that can be related with the reduction of oxidative damage and that it could be effective in therapeutic applications.

Background: RC-3095, a synthetic gastrin-releasing peptide (GRP) antagonist, has been identified as a candidate compound for the treatment of tumor necrosis factor (TNF)-dependent chronic inflammatory conditions., Aim: The aim of this study was to evaluate the effects of RC-3095 in a rat model of ulcerative colitis., Methods: Ninety Wistar rats were included in the study. Colitis was induced by a single intracolonic application of acetic acid. Rats were divided into three groups of treatment: subcutaneous RC-3095, intracolonic mesalazine, and subcutaneous dexamethasone. Additionally, there was a fourth group of animals submitted to induction of colitis without receiving any form of treatment, and a fifth group in which no colitis was induced. Seventy-two hours after instillation of acetic acid, the animals were killed and the following parameters were assessed: morphological score of damage, histological score of colonic inflammation, and immunohistochemical expression of TNF-alpha and interleukin (IL)-1beta., Results: RC-3095 was the only treatment to significantly reduce macroscopic and microscopic scores of inflammation as compared with the animals from the non-treated colitis group. RC-3095 also significantly reduced the colonic expression of TNF-alpha, but not the expression of IL-1beta., Conclusions: RC-3095 reduced the colitis severity in a well-established experimental model of IBD. The anti-inflammatory activity of this compound was associated with a reduction in the colonic expression of TNF-alpha. These results suggest that interference with GRP pathway might represent a potential new strategy for the treatment of ulcerative colitis that deserves further investigational studies.

The pathogenesis of sepsis is characterized by an overwhelming systemic inflammatory response that can lead to multiple organ failure. Considering that we have recently demonstrated that mitochondrial respiratory chain and creatine kinase (CK) are altered in the brain of rats after cecal ligation and perforation (CLP) and that a combination of N-acetylcysteine/deferoxamine (NAC/DFX), taurine and RC-3095 were shown to be an effective treatment of sepsis, we investigated whether the alterations of these enzymes may be reversed by these drugs. The results demonstrated that CLP inhibited complexes I and II, and that all the treatments were able to reverse this inhibition in all brain areas studied in the present work. On the other hand, complexes III and IV were not affected by sepsis neither by any of the treatments. An increase in CK activity in brain of rats 12 h after CLP was also verified; the administration of NAC/DFX and taurine reversed the increase in CK activity in hippocampus, cerebral cortex, cerebellum and striatum. On the other hand, RC-3095 significantly decreased CK activity, when compared to sham group in all brain areas studied. This is a preliminary study which showed beneficial effects of the treatments we proposed.

Previous studies have suggested that bipolar disorder may be associated with oxidative stress. Administration of D: -amphetamine (AMPH) has been put forward as an animal model of mania, and has shown to increase oxidative stress parameters in the rat brain. Thus, we have used the gastrin-releasing peptide receptor antagonist [D-Tpi(6)Leu(13)psi (CH(2)NH)-Leu(14)] bombesin (RC-3095) as a pharmacological tool to investigate the role of bombesin-like peptides in the redox balance in the hippocampus and cortex of rats treated with AMPH. Rats were given a single 10 ml/kg intraperitoneal (i.p.) injection of saline (SAL) or RC-3095 (0.1, 1.0 or 10.0 mg/kg) followed by an i.p. injection of SAL or amphetamine (AMPH 2.0 mg/kg) 30 min later. Locomotor activity was evaluated 2 h after the last drug injection. The thiobarbituric acid reactive substances (TBARS), protein carbonyl formation, superoxide dismutase and catalase (CAT) activity were measured in hippocampus, striatum and cortex as markers of oxidative stress. The results show that RC-3095 blocks AMPH-induced hyperlocomotion. Moreover, specific doses of RC-3095 alone increased the levels of oxidative stress in the dorsal hippocampus and cortex. However, when AMPH was subsequently administrated, RC-3095 decreased TBARS and protein carbonyls formation and increased the superoxide dismutase and CAT activity in the hippocampus, striatum and cortex. The effects of GRPR antagonist seemed to be region and dose specific. In conclusion, the results suggest that GRPR antagonists might display antioxidant properties in the brain.

Purpose: Some studies have shown the role of gastrin-releasing peptide (GRP) on the production and release of cytokines both in animal models and in humans with inflammatory diseases, but there are no reports on the effects of GRP in ocular inflammatory disease, mainly uveitis. The authors report on the effects of the GRP receptor (GRPR) antagonist RC-3095 in a well-established model for uveitis induced by the administration of lipopolysaccharide (LPS), comparing its effects with those of glucocorticoids., Methods: Adult male Wistar rats (weight range, 250-300 g; n = 6 per group) were randomly divided into four groups: saline, LPS + saline, LPS + dexamethasone, LPS + RC-3095. Two hours after LPS administration, RC-3095 (0.3 mg/kg, single dose, subcutaneously) or dexamethasone (1 mg/kg, each 6 hours, subcutaneously) was administered. After 24 and 48 hours, rats were anesthetized, aqueous humor was sampled, and the irides were removed. Aqueous humor tumor necrosis factor-alpha, monocyte chemoattractant protein-1 concentration, myeloperoxidase activity were determined. In addition, oxidative damage to the irides was determined by the measure of thiobarbituric acid reactive substances and protein carbonyl content., Results: The acute administration of RC-3095 exhibited anti-inflammatory actions, characterized by a reduction of myeloperoxidase activity and a decrease in tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels, to a greater extent than dexamethasone. In addition, RC-3095 elicits important action against irides oxidative damage., Conclusions: These findings suggest that GRP participates in the inflammatory response in an animal model of uveitis, making GRPR a target for new therapeutic options in the treatment of uveitis.

It has been proposed that reactive oxygen species play a causative role of gastric mucosal damage induced by increased gastric secretion. Gastrin-releasing peptide is a typical neuropeptide that stimulates acid secretion by release of gastrin. In the present work we have investigated the mechanism of indomethacin (IDM)-induced gastric ulcer caused by ROS and determined the effects of a selective gastrin-releasing peptide receptor antagonist, RC-3095, alone and in association with omeprazole (OM) and compared it with an established antioxidant compound N-acetyl cysteine (NAC). Adult male Wistar rats were pre-treated for 7 days with OM, RC-3095, NAC, both drugs and water (control). The animals were then submitted to fasting for 24h; IDM was administered. Rats were killed 6h after that and the stomachs were used for evaluation of macroscopic damage and oxidative stress parameters. Our results showed that IDM increased mitochondrial superoxide production; OM and RC-3095 alone did not prevent such effect, but the combination of these drugs was effective. TBARS assay revealed that IDM-induced lipid peroxidation in gastric tissue and that OM and RC-3095, alone or in combination, prevented this effect with superior action that NAC. Finally, we verified that IDM increased protein carbonyl content and that this effect was prevented RC-3095, alone or in combination with OM, being similar to standard antioxidant. The present results support the view that, besides the inhibition of acid secretion, the protective effects exerted by OM and RC-3095 against IDM-induced gastric damage can be ascribed to a reduction of gastric oxidative injury.

Gastrin-releasing peptide (GRP) acts as an autocrine growth factor for neuroblastoma and other types of cancer, and its cell-surface receptor, GRPR, is overexpressed in advanced-stage human neuroblastoma. GRPR knockdown and GRPR antagonism inhibit the growth of experimental neuroblastoma. Here we show that a GRPR antagonist promotes rather than inhibits the growth of neuroblastoma cells. The GRPR antagonist, RC-3095, at 0.1 nM inhibited, whereas at 100 nM stimulated proliferation of Neuro2a murine neuroblastoma cells in vitro. The stimulatory effects were prevented by the histone deacetylase inhibitor (HDACi), sodium butyrate (NaB). Expression of GRPR mRNA in Neuro2a cells was analyzed by RT-PCR. These findings provide evidence that a GRPR antagonist can stimulate the growth of cancer cells, and suggest that GRPR might interact with epigenetic mechanisms in regulating neuroblastoma cell growth.

Malignant gliomas have a dismal prognosis despite multi-modality treatments like neurosurgical resection, radiation therapy and chemotherapy. Evidence has indicated that gastrin-releasing peptide (GRP) and its receptor (GRPR) play a role in the development of a variety of cancers including gliomas. In the present study, we investigated the effects of RC-3095, a selective GRPR antagonist, alone or in combination with temozolomide (TMZ), a DNA alkylating agent, in in vitro and in vivo experimental rat C6 glioma models. Cellular proliferation was significantly reduced by all treatments with the combined administration of TMZ and RC-3095 being the most effective treatment. In in vivo experiments, the control group displayed the largest tumors (52 +/- 15.5 mm(3)), whereas RC-3095 reduced the tumor size, with the most significant effect at the dose of 0.3 mg/kg (21 +/- 9.7 mm(3)). The combined therapy produced further reduction in tumor size (10 +/- 7.5 mm(3)). Our results show that the combination of RC-3095 with TMZ produced an important reduction in in vitro and in vivo glioma growth therefore making RC-3095 a candidate drug to potentiate the effects of the DNA alkylating agent TMZ in the treatment of glioma.

Increasing evidence indicates that the neuronal gastrin-releasing peptide-preferring bombesin receptor (GRPR) is a key molecular regulator of fear memory formation. However, the downstream signaling events remain poorly understood. The protooncogene product phosphoinositide 3-kinase (PI3K) has been implicated in regulating memory formation, as well as in mediating cellular responses to GRPR activation in glioma and neuroblastoma cells. We show here that GRPR modulation of fear memory consolidation in the rat hippocampus requires PI3K activation. Male Wistar rats received bilateral infusions of the GRPR agonist bombesin (BB) or the PI3K inhibitor LY294002 into the CA1 region of the dorsal hippocampus immediately after inhibitory avoidance (IA) conditioning. BB enhanced, whereas LY294002 impaired, IA memory retention. The BB-induced memory enhancement was blocked by coinfusion of either a GRPR antagonist or LY294002. These findings provide the first evidence suggesting that PI3K signaling is required for GRPR regulation of CNS function.

The gastrin-releasing peptide receptor (GRPR) is a therapeutic target in colon cancer. Here we show that the GRPR antagonist RC-3095 (10(-3), 10(-6), or 1 microM) decreases nerve growth factor (NGF) secretion measured by enzyme-linked immunosorbent assay (ELISA) in HT-29 human colon carcinoma cells. The results suggest that decreased secretion of neurotrophins might be a novel mechanism by which GRPR antagonists exert their antiproliferative effects in cancer cells.

The gastrin-releasing peptide receptor (GRPR) has emerged as a novel molecular target in neurological and psychiatric disorders, and previous animal studies suggest that GRPR antagonists might display cognitive-enhancing and antipsychotic properties. Hyperlocomotion produced by administration of D-amphetamine (D-AMPH) to rats has been put forward as a model of the manic phase of bipolar disorder (BD). In the present study, we examined the effects of a single systemic administration of the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095) on hyperlocomotion induced by a single systemic injection of D-AMPH in male rats. We also evaluated the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of rats treated with D-AMPH and RC-3095. Administration of RC-3095 at any of the doses used blocked D-AMPH-induced hyperlocomotion. Specific doses of RC-3095 increased the levels of NGF and BDNF in the dorsal hippocampus. Administration of D-AMPH did not affect NGF or BDNF levels by itself, but blocked the RC-3095 effects. The results suggest that GRPR antagonists might display anti-manic activity.

Although the gastrin-releasing peptide receptor (GRPR) has recently emerged as a system importantly involved in regulating memory formation, the role of hippocampal GRPRs in memory remains controversial. The present study examined the effects of GRPR antagonism on memory consolidation in area CA1 of the hippocampus. Male Wistar rats received bilateral infusions of the GRPR antagonist [D-Tpi6, Leu13 psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095; 1, 3, or 10 microg/side) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. RC-3095 at 1 microg impaired, whereas the dose of 10 microg enhanced, 24-h IA retention. A second experiment showed that the RC-3095-induced enhancement of memory consolidation was prevented by pretraining infusion of an otherwise ineffective dose of the gamma-aminobutyric acid type A (GABA(A)) receptor agonist muscimol. The results indicate that high doses of GRPR antagonists can induce enhancement of memory consolidation in the hippocampus. In addition, the memory-enhancing effect of GRPR antagonists might be mediated by inhibition of GABAergic transmission.

Rationale: Several new therapeutic strategies have been described for the treatment of sepsis, but to date none are related to alterations in the bombesin/gastrin-releasing peptide (GRP) receptor pathways., Objectives: To determine the effects of a selective GRP receptor antagonist, RC-3095, on cytokine release from macrophages and its in vivo effects in the cecal ligation and puncture (CLP) model of sepsis and in acute lung injury induced by intratracheal instillation of LPS., Methods: We determined the effects of RC-3095 in the CLP model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. In addition, we determined the effects of RC-3095 on tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and nitric oxide release from activated macrophages., Measurements and Main Results: The GRP antagonist attenuated LPS- or CLP-induced TNF-alpha, IL-1beta, and nitric oxide release in cultured macrophages and decreased the mRNA levels of inducible nitric oxide synthase. The administration of RC-3095 (0.3 mg/kg) 6 h after sepsis induction improved survival in the CLP model, and diminished lung damage after intratracheal instillation of LPS. These effects were associated with attenuation on the circulating TNF-alpha and IL-1beta levels and decreased myeloperoxidase activity in several organs., Conclusions: We report that a selective GRP receptor antagonist attenuates the release of proinflammatory cytokines in vitro and in vivo and improves survival in "established" sepsis. These are consistent with the involvement of a new inflammatory pathway relevant to the development of sepsis.

The gastrin-releasing peptide receptor (GRPR) has been implicated in the modulation of emotionally-motivated memory. In the present study, we investigated the role of the GRPR on non-emotional, non-associative memory, and anxiety. Adult male Wistar rats were given a systemic injection of the GRPR antagonist [D-Tpi6, Leu(13) psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095) (0.2, 1.0 or 5.0mg/kg) 30 min before exposure to an open field or an elevated plus maze. Habituation to the open field was tested in a retention trial carried out 24 h after the first exposure to the open field. Rats given RC-3095 at the doses of 1.0 or 5.0mg/kg showed impaired habituation. Animals treated with 5.0mg/kg of RC-3095 spent significantly more time in the closed arms of the elevated plus maze. No effects of RC-3095 on locomotion or exploratory behavior were observed. The results implicate the GRPR in the regulation of non-emotional, non-associative memory as well as in anxiety.

Bombesin (BN) and its mammalian equivalent, gastrin-releasing peptide (GRP), stimulate cell proliferation and are involved in the pathogenesis of several types of human cancer. BN/GRP and their receptors were shown to be critical for the growth of various human malignancies, such as small-cell lung, prostate, ovary, stomach and breast cancers in the human tumor xenograft model. In the present study, a fast, sensitive, robust method was developed for the determination and quantification of a BN/GRP receptor antagonist RC-3095 (D-Tpi-Gln-Trp-Ala-Val-Gly-His-Leupsi(CH2NH)Leu-NH2), in human plasma by liquid chromatography coupled with tandem mass spectrometry. RC-3095 was extracted from 0.2 ml human plasma by protein precipitation using cold acetonitrile (0.4 ml). The method has a chromatographic run of 10 min using a C(8) analytical column (150 mm x 4.6 mm i.d.) and the linear calibration curve over the range was linear from 20 to 10000 ng ml(-1) (r(2)>0.994). The between-run precision, based on the relative standard deviation replicate quality controls, was 5.7% (60 ng ml(-1)), 7.1% (600 ng ml(-1)) and 6.8% (8000 ng ml(-1)). The between-run accuracy was +/-0.0, 2.1 and 3.1% for the above-mentioned concentrations, respectively. The developed procedure allows the quantitative determination of peptide RC-3095 for pharmacokinetics studies in human plasma.

Bombesin (BN)-like peptides might be involved in the pathogenesis of neuropsychiatric disorders such as schizophrenia. Stereotyped behaviors induced by the dopamine receptor agonist apomorphine or the N-methyl-D-aspartate glutamate receptor antagonist dizocilpine (MK-801) in rodents have been proposed as animal models of schizophrenic psychosis. In the present study we evaluated the effects of the BN/gastrin-releasing peptide receptor (GRP) antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) on apomorphine and MK-801-induced stereotyped behavior in mice. An intraperitoneal (i.p.) injection of RC-3095 (1.0, 10.0 or 100.0 mg/kg) blocked apomorphine-induced stereotypy. The inhibitory effect of RC-3095 on apomorhine-induced stereotypy was similar to that induced by haloperidol (0.5 mg/kg). RC-3095 did not affect stereotyped behavior induced by MK-801 (0.5 mg/kg). The results provide the first evidence that BN/GRP receptor antagonism blocks stereotyped behavior induced by a dopamine agonist. Together with previous evidence, the present study indicates that the BN/GRP receptor can be considered a drug target in the investigation of potential new agents for treating neuropsychiatric disorders., (Copyright 2004 Elsevier Inc.)

Bombesin and its mammalian equivalent, gastrin-releasing peptide (GRP), stimulate cell proliferation and are involved in the pathogenesis of several types of human cancer. Bombesin-like peptides also display neuroendocrine activities and regulate neural function. In the present study, we evaluated the effects of the bombesin/GRP receptor antagonist (D-Tpi(6), Leu(13) psi[CH(2)NH]-Leu(14)) bombesin-(6-14) (RC-3095), experimental antitumor drug, on memory in rats. Adult female Wistar rats were treated with an intraperitoneal injection of RC-3095 (0.2, 1.0 or 5.0 mg/kg) 30 min before training in either inhibitory avoidance or novel object recognition tasks. Retention test trials were carried out 1.5 (short-term memory) or 24 h (long-term memory) after training. RC-3095 at the doses of 0.2 or 1.0 mg/kg, but not at the dose of 5.0 mg/kg, impaired both short- and long-term inhibitory avoidance retention, but did not affect recognition memory. The memory-impairing effect of RC-3095 could not be attributed to alterations in sensorimotor functions. The results show that the antitumor drug/GRP antagonist RC-3095 impairs formation of aversive memory.

Several receptor and intracellular signalling systems in the basolateral amygdala (BLA) regulate memory formation. In the present study, we show that bombesin/gastrin-releasing peptide (GRP) receptors in the BLA are involved in the consolidation of affectively motivated memory. Adult male rats were trained in a single-trial step-down inhibitory avoidance task and tested for retention 24 h later. Post-training systemic injection of the bombesin/GRP receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) impaired memory retention. In rats implanted under thionembutal anaesthesia with guide cannulae aimed at the BLA, post-training bilateral infusion of RC-3095 into the BLA dose-dependently impaired retention. Pre-training unilateral muscimol inactivation of the BLA blocked the memory-impairing effect of post-training systemic administration of RC-3095. The results suggest that bombesin/GRP receptors in the BLA are involved in the consolidation of aversive memory, and the BLA mediates the memory-impairing effect of systemic bombesin/GRP receptor blockade.

Bombesin (BN)-like peptides regulate cell proliferation and cancer growth as well as neuroendocrine and neural functions. We evaluated the effects of the BN/gastrin-releasing peptide (GRP) antagonist RC-3095 on memory formation. Male Wistar rats were given a bilateral infusion of saline or RC-3095 (0.2, 1.0 or 5.0 microg) into the dorsal hippocampus either immediately or 2 h after training in an inhibitory avoidance (IA) task. Retention test trials were carried out 1.5 h (short-term memory) and 24 h (long-term memory) after training. RC-3095 impaired both short- and long-term retention only when given immediately after training. The results suggest that the hippocampal BN/GRP receptor system modulates IA memory formation.

Increasing evidence indicates that gastrin-releasing peptide (GRP) acts as an autocrine growth factor for brain tumors. However, it remains unclear whether the cAMP/protein kinase A (PKA) signaling pathway plays a role in mediating the mitogenic effects of GRP. We show here that GRP combined with agents that stimulate the cAMP/PKA pathway promotes proliferation of human gliobastoma cells. Treatment with GRP combined with the adenylyl cyclase activator forskolin, the cAMP analog 8-Br-cAMP or the phosphodiesterase type IV inhibitor rolipram increased proliferation of U138-MG cells in vitro measured by MTT assay. None of the compounds had an effect when given alone. GRP receptor (GRPR) mRNA and protein expression in U138-MG cells was detected by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. The results suggest that GRP and the GRPR interact with the cAMP/PKA signaling pathway in stimulating cancer cell proliferation. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: It was the aim of this study to evaluate whether cervical neoplasms and adjacent tissues express the gastrin-releasing peptide receptor (GRPR) and whether there is a significant difference in its distribution among preinvasive and invasive cancers. Methods: Sections of paraffin-embedded cervical tumors (n = 88) and non-neoplastic control cervical tissues (n = 14) obtained from women registered in the Pathology Department, Academic Hospital, Federal University of Rio Grande do Sul, Porto Alegre, Brazil, were investigated by immunohistochemistry for GRPR. Results: GRPR was detected in 99% of tumor specimens, mostly exhibiting a diffuse strong staining. The receptors were seldom detected in the endocervices, while ectocervices expressed GRPRs only when adjacent to neoplastic lesions. No correlation between GRPR expression and preinvasive and invasive neoplasms was found. Conclusions: To the best of our knowledge, this is the first demonstration of the widespread GRPR expression in human cervical cancer. The presence of receptors both in tumors and surrounding tissues may suggest that GRPR can play a role in the cervical carcinogenic process. These data provide a molecular basis for exploiting GRPR as a target for diagnostic and therapeutic purposes in cervical neoplasms. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]