Determination of docetaxel in dried blood spots by LC-MS/MS: Method development, validation and clinical application.

In this study, a LC-MS/MS method for the measurement of docetaxel in Dried Blood Spots (DBS) samples was developed and validated. Docetaxel was extracted from 8 mm DBS punch with a mixture of methanol and acetonitrile (9:1, v/v). The chromatographic separation occurred in an Acquity® C18 column (150 × 2.1 mm, 1.7 µm) eluted with a mixture of water and acetonitrile plus 0.1% formic acid (45:55, v/v). Total analytical run time was 7 min. The method was linear from 50 to 3000 ng ml-1. Precision assays showed CV% < 9.8% and accuracy between 99 and 103%, mean recovery was 81%. The method was applied in the determination of the docetaxel in 31 patients, after collection of two paired venous blood and DBS samples, following a limited sampling strategy protocol. The analyte was stable in DBS for 18 days at 25 °C and 9 days at 45 °C. The interval of docetaxel concentrations measured in DBS collected before the end of the infusion was 756-3047 ng ml-1 and 60 ±â€¯10 min after the end of the infusion was 57-331 ng ml-1. AUC values calculated from DBS-derived estimated plasma concentrations (EPC) represented on average 100% of those obtained in plasma samples of 3.1 mgh/l (2.4-4.9 mg h/l). There was a 93% agreement between the classification of patients as within or without the therapeutic range by plasma and EPC AUC. These findings support the clinical use of DBS sampling for routine therapeutic drug monitoring of docetaxel.

DEFB1 gene 5' untranslated region (UTR) polymorphisms are marginally involved in inflammatory bowel disease in south Brazilians.

The possible association of three DEFB1 gene polymorphisms with susceptibility to develop ulcerative colitis (UC) and Crohn's disease (CD) was investigated in Brazilian patients and controls. Although a clear and strong association between functional 5'-UTR DEFB1 SNPs and susceptibility/protection to IBDs cannot be drawn, our results suggest a possible involvement of DEFB1 gene in inflammatory bowel diseases, especially with the colonic localization of Crohn's disease.

Expression of gastrin-releasing peptide receptor in patients with cutaneous malignant melanoma.

BACKGROUND: Gastrin-releasing peptide (GRP) is a neuroendocrine peptide shown to possess growth-stimulatory effects in many types of human cancers. High levels of GRP receptors have been found in various types of human cancers, and preclinical studies exploring the therapeutic use of GRP receptor (GRPR) antagonists have been reported, with promising results. Data on GRPR expression in human malignant melanoma (MM) are scanty. AIM: To determine GRPR expression in biopsy material obtained from patients diagnosed with cutaneous MM. METHODS: Immunohistochemistry was performed on formalin-fixed, paraffin wax-embedded tissue samples obtained from 51 patients with cutaneous MM. The relationship between GRPR expression and the clinicopathological features was analysed using the Fisher exact test. RESULTS: GRPR immunoexpression was found in 42/51 cutaneous melanoma samples (82.4%). It was strongly expressed in 30 cases (58.9%). There was no significant difference in the levels of GRPR expression between primary or metastatic lesions. We correlated the GRPR expression score with pathological features associated with prognosis in cutaneous MM. There was no significant difference in GRPR expression in relation to Clark level (CL; P = 0.35) or Breslow Index (BI; P = 0.17). CONCLUSIONS: GRPR expression levels were high in tissue specimens of MM (82.4%), but did not correlate with pathological features related to prognosis, such as CL or BI. Further studies, preferably in a larger patient population, are warranted.

Analysis of KIR gene frequencies and HLA class I genotypes in prostate cancer and control group.

Prostate cancer is the second most common cancer in men, with a significant increase in incidence and mortality in men over 50 years of age. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with prostate cancer and healthy controls. Two hundred patients with prostate cancer and 185 healthy controls were typed for HLA class I and KIR genes by PCR-SSP. When both groups were compared, no significant differences were found for HLA-C group 1 and group 2, HLA-Bw4, HLA-A3 and A11. No difference was seen either in KIR frequency between patients with prostate cancer and controls. In conclusion, our data suggest no potential role for the KIR gene system in prostate cancer.

Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis.

OBJECTIVE: To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved. METHODS: RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1ß, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA. RESULTS: In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1ß, and TNFα, and showed a diminished expression of GRPR. CONCLUSION: These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.

Recent therapeutic advances for treating medulloblastoma: focus on new molecular targets.

Medulloblastoma is the most common malignant brain tumor in children. This malignant tumor of the cerebellum commonly affects children and is believed to arise from the precursor cells of the external granule layer or neuroepithelial cells from the cerebellar ventricular zone of the developing cerebellum. The standard treatment, consisting of surgery, craniospinal radiotherapy and chemotherapy, still provides a poor overall survival for infants and young children. Furthermore, the dose of radiation that can be safely given without causing extensive neurocognitive and endocrinologic sequelae is limited. Therefore, understanding the oncogenic pathways that lead to medulloblastoma, as well as the identification of specific molecular targets with significant therapeutic implications in order to develop new strategies for therapy, is crucial to improve patient survival without substantially increasing toxicity. In this review, we discuss recent therapeutics for treating medulloblastoma, focusing on new molecular targets, as well as advances in translational studies for the treatment of this malignancy.

Killer cell immunoglobulin-like receptor gene diversity in a Caucasian population of southern Brazil.

Killer immunoglobulin-like receptors (KIR) regulate the activity of natural killer and T cells through an interaction with specific human leucocyte antigen (HLA) class I molecules on target cells. Diversity in KIR gene content, KIR allelic and haplotype polymorphism has been observed between different ethnic groups. However, most population studies on KIR variability have focused on Europe and Asia, while Americas, Oceania and Africa remain poorly studied. The aim of this study was to analyse the variability of KIR genes in 200 healthy nonrelated individuals from the Southern Brazilian population. KIR genes and HLA-A, -B and -Cw were genotyped using polymerase chain reaction-sequence-specific primers. Southern Brazilian population demonstrated several similarities to states that are closer geographically and distinct differences with Northern Brazil in the frequency of genes KIR2DS1, 2DS2, 2DS3, 2DS5, 3DL1, 3DS1, 2DL1 and 2DL2. The activating gene KIR2DS5 was the least frequent locus found in our group. Interaction of KIR/HLA was more common in the 2DS1-/2DL1+/C2+ association. This study demonstrated the diversity of KIR genes and of KIR/HLA association in a Caucasian group of Southern Brazil, establishing differences and similarities to other different populations.

Breast cancer in Latin America: experts perceptions compared with medical care standards.

BACKGROUND: The BCRF II study presents a systematic review of the norms, recommendations and guidelines that are considered medical care standards (MCS) for breast cancer in 12 Latin American and Caribbean countries. Three key questions from the BCRF I survey data on early detection and diagnosis are presented to identify implementation practice patterns related to MCS. METHODS: Information related to MCS was requested from governmental health authorities, cancer institutes, and national scientific and professional societies in 12 Latin American and Caribbean countries. Documents received were reviewed by breast cancer experts from each respective country. Three key survey questions from the BCRF I survey on early detection and diagnosis were reprocessed to provide information related to implementation practice of existing MCS. RESULTS: All countries included in the BCRF II study had medical care standards (MCS) whether published by governmental authorities, national professional or scientific associations, cancer institutes, or adoption of international MCS. Experts reported different practice patterns at a Country level versus a Center level. Overall, 85% of the experts reported that less than 50% of the women with no symptoms undergo a mammography at the Country level compared to 43% at the Center level. For diagnostic suspicion of breast cancer, 80% of experts considered the diagnostic suspicion at a Country level to come from the patient compared to 50% at a Center level. About 30% of patients waited for more than 3 months for a diagnosis at the Country level compared to 7% at the Center level. CONCLUSION: All the Latin America and Caribbean countries in the study reported the use of similar MCS for breast cancer care. The reported difference between care practiced at a Country level versus a Center level suggests the challenge is not in generating new MCS, but in implementing policies and control mechanisms for compliance with existing MCS, guaranteeing their applicability to all populations.

The effects of sample size on the outcome of ovarian tissue cryopreservation.

Cryopreservation of ovarian tissue is known to affect follicular survival. Several variables may be responsible for this. Little attention has focused on the effect of the size of the fragment to be cryopreserved. This study was conducted to assess the effect of the size of the tissue on follicular histology after freezing with 1,2-propanediol. Histological evaluations were performed of control and cryopreserved tissue. Fragments were cut 10 x 3 x 2 mm(3) (2 mm group) or 10 x 3 x 4 mm(3) (4 mm group). Percentages of normal follicles in control fragments cut into 2 and 4 mm slices were 56% and 34%, respectively. The relative risks to obtain normal follicles in the 2 mm and the 4 mm fragments after cryopreservation were 0.63 and 0.47, respectively. Freezing reduced follicle survival to a significantly greater extent in the larger tissue fragments. There is an increased risk of damage to primary and primordial follicles, when the tissue slices are cut with all dimensions larger than 2 mm.

Prevalence of vascular-endothelial growth factor, matrix metalloproteinases and tissue inhibitors of metalloproteinases in primary breast cancer

Our objective was to determine the presence of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and MMP-9 and specific tissue inhibitors of matrix metalloproteinase (TIMP-1 and TIMP-2) in tumor samples obtained from patients with primary breast cancer. We attempted to correlate these findings with the status of the sentinel lymph node (SLN) and clinical-pathological characteristics such as age, tumor size, histological type, histological grade, and vascular invasion. Tumor samples from 88 patients with primary breast cancer were analyzed. The immunoreactivity of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 in tumors was correlated with clinical and pathological features, as well as SLN status. Nonparametric, Mann-Whittney, Kruskal-Wallis, and Spearmann tests were used. Categorical variables were analyzed by the Pearson test. No statistically significant correlation was found between the amount of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 and the presence of tumor cells in the SLN. However, larger tumor diameter (P < 0.01) and the presence of vascular invasion (P < 0.01) were correlated positively with a positive SLN. A significant correlation of higher VEGF levels (P = 0.04) and lower TIMP-1 levels (P = 0.04) with ductal histology was also observed. Furthermore, lower TIMP-2 levels showed a statistically significant correlation with younger age (<50 years) and larger tumor diameter (2.0-5.0 cm). A positive SLN correlated significantly with a larger tumor diameter and the presence of vascular invasion. Higher VEGF and lower TIMP-1 levels were observed in patients with ductal tumors, while higher TIMP-1 levels were observed in lobular tumors.

Prevalence of vascular-endothelial growth factor, matrix metalloproteinases and tissue inhibitors of metalloproteinases in primary breast cancer.

Our objective was to determine the presence of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and MMP-9 and specific tissue inhibitors of matrix metalloproteinase (TIMP-1 and TIMP-2) in tumor samples obtained from patients with primary breast cancer. We attempted to correlate these findings with the status of the sentinel lymph node (SLN) and clinical-pathological characteristics such as age, tumor size, histological type, histological grade, and vascular invasion. Tumor samples from 88 patients with primary breast cancer were analyzed. The immunoreactivity of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 in tumors was correlated with clinical and pathological features, as well as SLN status. Nonparametric, Mann-Whittney, Kruskal-Wallis, and Spearmann tests were used. Categorical variables were analyzed by the Pearson test. No statistically significant correlation was found between the amount of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 and the presence of tumor cells in the SLN. However, larger tumor diameter (P < 0.01) and the presence of vascular invasion (P < 0.01) were correlated positively with a positive SLN. A significant correlation of higher VEGF levels (P = 0.04) and lower TIMP-1 levels (P = 0.04) with ductal histology was also observed. Furthermore, lower TIMP-2 levels showed a statistically significant correlation with younger age (<50 years) and larger tumor diameter (2.0-5.0 cm). A positive SLN correlated significantly with a larger tumor diameter and the presence of vascular invasion. Higher VEGF and lower TIMP-1 levels were observed in patients with ductal tumors, while higher TIMP-1 levels were observed in lobular tumors.

Cáncer de mama Latinoamericano / Breast cancer in Latin America

La incidencia del cáncer de mama en países latinoamericanos es menor que en países más desarrollados, mientras que la tasa de mortalidad es mayor. Estas diferencias están relacionadas probablemente con diferencias en estrategias de despistaje y acceso al tratamiento. Se necesitan datos basados en población a fin de que sea posible tomar decisiones informadas. En el año 2006 se llevó a cabo una encuesta telefónica de 65 preguntas, que incluyó a 100 expertos en cáncer de mama de 12 países latinoamericanos, efectuando un análisis exploratorio del estado actual del tratamiento de cáncer de mama en estas regiones, tanto a nivel país como a nivel centro. Más del 90% de los países no tienen ley nacional o guía para screening mamográfico. La tasa de acceso a mamografía fue del 66,3% a nivel país y del 47,0% a nivel centro. La diferencia en la atención, basada en el nivel (país versus centro), fue indicada por la iniciación del tratamiento luego del diagnóstico, el tiempo desde el diagnóstico inicial al tratamiento y el tiempo desde la cirugía hasta la quimioterapia inicial. Sin embargo, las pruebas diagnósticas más sofisticadas para receptores hormonales y moleculares están disponibles en la mayoría de los centros (>80%), y en total, casi el 80% de las pacientes comenzaron el tratamiento dentro de los 3 meses del diagnóstico. La variación en la atención entre el nivel del centro versus el nivel del país para la atención del cáncer de mama, indica una necesidad de programas nacionales para el cuidado del cáncer. También se concluye que son necesarias estrategias alternativas de recolección de datos, a fin de comprender mejor el estado de los programas de control del cáncer de mama en países en desarrollo

Cáncer de mama Latinoamericano / Breast cancer in Latin America

La incidencia del cáncer de mama en países latinoamericanos es menor que en países más desarrollados, mientras que la tasa de mortalidad es mayor. Estas diferencias están relacionadas probablemente con diferencias en estrategias de despistaje y acceso al tratamiento. Se necesitan datos basados en población a fin de que sea posible tomar decisiones informadas. En el año 2006 se llevó a cabo una encuesta telefónica de 65 preguntas, que incluyó a 100 expertos en cáncer de mama de 12 países latinoamericanos, efectuando un análisis exploratorio del estado actual del tratamiento de cáncer de mama en estas regiones, tanto a nivel país como a nivel centro. Más del 90% de los países no tienen ley nacional o guía para screening mamográfico. La tasa de acceso a mamografía fue del 66,3% a nivel país y del 47,0% a nivel centro. La diferencia en la atención, basada en el nivel (país versus centro), fue indicada por la iniciación del tratamiento luego del diagnóstico, el tiempo desde el diagnóstico inicial al tratamiento y el tiempo desde la cirugía hasta la quimioterapia inicial. Sin embargo, las pruebas diagnósticas más sofisticadas para receptores hormonales y moleculares están disponibles en la mayoría de los centros (>80%), y en total, casi el 80% de las pacientes comenzaron el tratamiento dentro de los 3 meses del diagnóstico. La variación en la atención entre el nivel del centro versus el nivel del país para la atención del cáncer de mama, indica una necesidad de programas nacionales para el cuidado del cáncer. También se concluye que son necesarias estrategias alternativas de recolección de datos, a fin de comprender mejor el estado de los programas de control del cáncer de mama en países en desarrollo

Sodium butyrate enhances the cytotoxic effect of antineoplastic drugs in human lymphoblastic T-cells.

Sodium butyrate (NaB), a potent histone deacetylase inhibitor, induces cell cycle arrest and apoptosis in malignant cells. We investigated the effects on cellular proliferation in vitro when combining NaB with antineoplastic drugs commonly used to treat leukemias. Our results demonstrate that NaB increases the cytotoxic effects of cytarabine and etoposide, but not of bleomycin, doxorubicin, vincristine or methotrexate. These data suggest that NaB is a promising adjuvant therapeutic agent for the treatment of lymphoblastic leukemias, and provides a basis for further studies in this field.

A study of the killer cell immunoglobulin-like receptor gene KIR2DS1 in a Caucasoid Brazilian population with psoriasis vulgaris.

Psoriasis is a chronic inflammatory skin disease whose pathogenesis and genetic background remain unclear. Considering that previous studies have suggested an association of psoriasis vulgaris (PV) and killer cell immunoglobulin-like receptors (KIRs), we typed 15 KIR genes and human leukocyte antigen (HLA)-Cw in 79 Brazilian Caucasoid patients with PV and 110 healthy controls by polymerase chain reaction (PCR) using sequence-specific oligonucleotides and sequence-specific primers. We did not observe a relevant increase in the frequency of the activating KIR2DS1 gene in the PV group [KIR2DS1, 46 of 79 cases (58.2%) vs 40 of 110 controls (36.4%)]. However, an association of KIR2DS1 with Cw*0602+ in 26.5% of PV patients was observed, while it was present in only 5.4% of controls. These results suggest that activating KIR2DS1 gene may not confer susceptibility to PV, and an association of KIR2DS1 gene with the HLA-Cw*0602+ was observed in these patients.

Effects of an antagonist of the bombesin/gastrin-releasing peptide receptor on complete Freund's adjuvant-induced arthritis in rats.

OBJECTIVE: To determine the effects of RC-3095 in clinical and histopathologic parameters and inflammatory mediators on complete Freund's adjuvant-induced arthritis (CFA). METHODS: The arthritis was induced by injection of CFA into the left hind footpad. The animals were divided into control, vehicle injected control, placebo group (saline subcutaneously 50ml/kg, once daily for 8 days after modeling), treatment group (0.3mg/kg of RC-3095 subcutaneously, once daily for 8 days after induction). Clinical evaluation was accomplished daily, through scoring of the paw edema. The animals were sacrificed 15 days after induction for collection of hind foot joints for histology. We used a histological scoring system which was previously described, and interferon (INF)-gamma, interleukin (IL)-1beta, tumor necrosis factor (TNF), interleukin (IL)-6 and interleukin (IL)-10 were measured by ELISA. RESULTS: There was a significant inhibition of joint histological findings in the RC-3095 treated group, including synovial inflammatory infiltration and hyperplasia, cartilage and bone erosion. IFN-gamma, IL-1beta, TNF, IL-6 and IL-10 serum levels were significantly lower in the treated group. Paw swelling and subcutaneous inflammation, evaluated clinically, were not different between CFA-induced groups. CONCLUSIONS: RC-3095 was able to improve experimental arthritis, attenuate joint damage and decrease serum levels of IFN-gamma, IL-1beta, TNF, IL-6 and IL-10. These data indicate that interference with GRP pathway is a potential new strategy for the treatment of RA that needs further investigational studies.

Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy.

Over the last two decades, several lines of experimental evidence have suggested that the gastrin-releasing peptide (GRP) may act as a growth factor in many types of cancer. For that reason, gastrin-releasing peptide receptor (GRPR) antagonists have been developed as anticancer candidate compounds, exhibiting impressive antitumoral activity both in vitro and in vivo in various murine and human tumors. In this article, the GRPR cell surface expression profile in human malignancies is reviewed aiming at the identification of potential tumor types for future clinical trials with GRP analogues and antagonists. In this review, we summarize the current literature regarding the GRPR status in human malignancies. Source data were obtained by searching all published material available through Medline, PubMed and relevant articles from 1971 to 2006. The data available demonstrated a high expression of GRPRs in a large spectrum of human cancers, demonstrating the potential relevance of this intracellular signaling pathway in various human tumor models. The GRPR may be an interesting target for therapeutic intervention in human malignancies, as carriers for cytotoxins, immunotoxins or radioactive compounds, being also a potential tool for tumor detection.

Evidence for an association of human papillomavirus infection and colorectal cancer.

AIM: To investigate the presence of human papillomavirus (HPV) in colorectal carcinomas and the correlation of the viral infection with prognostic factors for the disease outcome. METHODS: Seventy-two patients with primary colorectal adenocarcinoma were studied. From each patient two tissue samples were collected: one sample of the tumor and one sample of normal colorectal tissue from an area located 15 cm away from the tumor. Samples of colorectal mucosa obtained from 30 individuals without malignant disease were also studied as control group. Tissues were initially analyzed through MY/GP nested polymerase chain reaction (PCR) and through GP5+/GP6+ auto-nested PCR. Specific primer sets targeting the E6/E7 region of the HPVs 6, 11, 16, 18, 31, 33, 45 were used for typing. Direct DNA sequencing was conducted to confirm positive PCR results. RESULTS: HPV DNA was detected in colorectal specimens of 60 patients with cancer (83.3%), but in none of the tissues from the non-malignant control group (p<0.001). Twenty-three cancer patients had HPV DNA detected in both the tumor and the matched normal tissue, 23 had HPV only in the tumor, and 14 had HPV only in the normal colorectal tissue. HPV16 was the viral type most frequently detected, being present in 41 out of 60 positive cases (68.3%). No correlation between the presence of the virus and specific prognostic predictors for the disease outcome was observed. CONCLUSION: HPV is present in the colon and rectum of most patients with colorectal adenocarcinoma, suggesting that this virus may be related to the pathogenesis of colorectal cancer.

Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders.

The gastrin-releasing peptide receptor (GRPR) has been implicated in central nervous system (CNS) diseases, including neurodevelopmental disorders associated with autism. In the present study we examined the effects of GRPR blockade during the neonatal period on behavioral measures relevant to animal models of neurodevelopmental disorders. Male Wistar rats were given an intraperitoneal (i.p.) injection of either saline (SAL) or the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095; 1 or 10mg/kg) twice daily for 10days from postnatal days (PN) 1 to 10. Animals treated with RC-3095 showed pronounced deficits in social interaction when tested at PN 30-35 and impaired 24-h retention of memory for both novel object recognition (NOR) and inhibitory avoidance (IA) tasks tested at PN 60-71. Neither short-term memory tested 1.5h posttraining nor open field behavior were affected by neonatal GRPR blockade. The implications of the findings for animal models of neurodevelopmental disorders are discussed.

Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus.

Although the gastrin-releasing peptide-preferring bombesin receptor (GRPR) has been implicated in memory formation, the underlying molecular events are poorly understood. In the present study, we examined interactions between the GRPR and cellular signaling pathways in influencing memory consolidation in the hippocampus. Male Wistar rats received bilateral infusions of bombesin (BB) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intermediate doses of BB enhanced, whereas a higher dose impaired, 24-h IA memory retention. The BB-induced memory enhancement was prevented by pretraining infusions of a GRPR antagonist or inhibitors of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) kinase and protein kinase A (PKA), but not by a neuromedin B receptor (NMBR) antagonist. We next further investigated the interactions between the GRPR and the PKA pathway. BB-induced enhancement of consolidation was potentiated by coinfusion of activators of the dopamine D1/D5 receptor (D1R)/cAMP/PKA pathway and prevented by a PKA inhibitor. We conclude that memory modulation by hippocampal GRPRs is mediated by the PKC, MAPK, and PKA pathways. Furthermore, pretraining infusion of BB prevented beta-amyloid peptide (25-35)-induced memory impairment, supporting the view that the GRPR is a target for the development of cognitive enhancers for dementia.