Histone deacetylase inhibition prevents the impairing effects of hippocampal gastrin-releasing peptide receptor antagonism on memory consolidation and extinction.

Hippocampal gastrin-releasing peptide receptors (GRPR) regulate memory formation and extinction, and disturbances in GRPR signaling may contribute to cognitive impairment associated with neurodevelopmental disorders. Histone acetylation is an important epigenetic mechanism that regulates gene expression involved in memory formation, and histone deacetylase inhibitors (HDACis) rescue memory deficits in several models. The present study determined whether inhibiting histone deacetylation would prevent memory impairments produced by GRPR blockade in the hippocampus.

Gastrin-Releasing Peptide Receptor Knockdown Induces Senescence in Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, characterized by excessive cell proliferation, resistance to apoptosis, and invasiveness. Due to resistance to currently available treatment options, the prognosis for patients with GBM is very dismal. The activation of gastrin-releasing peptide receptors (GRPR) stimulates GBM cell proliferation, whereas GRPR antagonists induce antiproliferative effects in in vitro and in vivo experimental models of GBM.

BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown.

Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists.

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.

TrkB blockade in the hippocampus after training or retrieval impairs memory: protection from consolidation impairment by histone deacetylase inhibition.

Relatively little is known about the requirement of signaling initiated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), in the early phases of memory consolidation, as well as about its possible functional interactions with epigenetic mechanisms. Here we show that blocking TrkB in the dorsal hippocampus after learning or retrieval impairs retention of memory for inhibitory avoidance (IA). More importantly, the impairing effect of TrkB antagonism on consolidation was completely prevented by the histone deacetylase (HDAC) inhibitor sodium butyrate (NaB).

P2X7 receptor as predictor gene for glioma radiosensitivity and median survival.

Glioblastoma multiforme (GBM) is considered the most lethal intracranial tumor and the median survival time is approximately 14 months. Although some glioma cells present radioresistance, radiotherapy has been the mainstay of therapy for patients with malignant glioma. The activation of P2X7 receptor (P2X7R) is responsible for ATP-induced death in various cell types.

Enhancement of memory consolidation by the histone deacetylase inhibitor sodium butyrate in aged rats.

Here we show that a systemic injection of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) immediately after training in a step-down inhibitory avoidance task produced an enhancement of memory consolidation that persisted across consecutive retention tests during 14 days in aged rats, while it did not significantly affect memory in young adults. Control aged and young adult rats showed comparable basal levels of memory retention. Our results suggest that HDACis can display memory-enhancing effects specific for aged animals, even in the absence of age-related memory impairment.

Two waves of proteasome-dependent protein degradation in the hippocampus are required for recognition memory consolidation.

Healthy neuronal function and synaptic modification require a concert of synthesis and degradation of proteins. Increasing evidence indicates that protein turnover mediated by proteasome activity is involved in long-term synaptic plasticity and memory. However, its role in different phases of memory remains debated, and previous studies have not examined the possible requirement of protein degradation in recognition memory.

Cisplatin induces Bmi-1 and enhances the stem cell fraction in head and neck cancer.

Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs). These unique cells, named here cancer stem cells (CSCs), proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6)] for their survival and self-renewal in HNSCC.

International scientific collaboration in HIV and HPV: a network analysis.

Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis.

A phosphodiesterase 4-controlled switch between memory extinction and strengthening in the hippocampus.

Established fear-related memories can undergo phenomena such as extinction or reconsolidation when recalled. Extinction probably involves the creation of a new, competing memory trace that decreases fear expression, whereas reconsolidation can mediate memory maintenance, updating, or strengthening. The factors determining whether retrieval will initiate extinction, reconsolidation, or neither of these two processes include training intensity, duration of the retrieval session, and age of the memory.

Basolateral amygdala activity is required for enhancement of memory consolidation produced by histone deacetylase inhibition in the hippocampus.

Histone acetylation, a type of chromatin modification that allows increased gene transcription and can be pharmacologically promoted by histone deacetylase (HDAC) inhibitors (HDACis), has been consistently associated with promoting memory formation in the hippocampus. The basolateral nucleus of the amygdala (BLA) is a brain area crucially involved in enabling hormones and drugs to influence memory formation. Here, we show that BLA activity is required for memory enhancement by intrahippocampal administration of an HDACi.

Long-term behavioral effects of neonatal blockade of gastrin-releasing peptide receptors in rats: similarities to autism spectrum disorders.

Gastrin releasing peptide, the mammalian counterpart of the amphibian peptide, bombesin, has been increasingly implicated in regulating normal brain function as well as in the pathogenesis of psychiatric and/or neurodevelopmental disorders. We have previously shown that the neonatal blockade of the gastrin-releasing peptide receptor (GRPr) in rats produces long-lasting consequences during central nervous system development that are commonly observed in neurodevelopmental disorders such as autism spectrum disorders. The present investigation assessed in further detail, long-term behavioral effects of neonatal GRPr blockade.

Gastrin-releasing peptide receptor expression in lung cancer.

Context: Gastrin-releasing peptide receptors (GRPRs) activate mitogen-activated protein kinase signaling pathway primarily through epidermal growth factor receptor activation and are under investigation as a molecular target because they are overexpressed in several solid tumors.

Objective: To determine GRPR expression in both non-small cell lung carcinoma and small cell lung carcinoma, comparing results with clinical stages and demographic data.

Design: We analyzed the immunohistochemical expression of GRPR in 200 non-small cell lung carcinoma and 38 small cell lung carcinoma archival cases from 2004 to 2008.

Evaluation of Na+, K+-ATPase activity in the brain of young rats after acute administration of fenproporex.

Objectives: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats.

Gastrin-releasing peptide receptor signaling in the integration of stress and memory.

Neuropeptides act as signaling molecules that regulate a range of aspects of brain function. Gastrin-releasing peptide (GRP) is a 27-amino acid mammalian neuropeptide, homolog of the amphibian peptide bombesin. GRP acts by binding to the GRP receptor (GRPR, also called BB2), a member of the G-protein coupled receptor (GPCR) superfamily.

Inhibition of protein synthesis or mTOR in the basolateral amygdala blocks retrieval-induced memory strengthening.

Fear memory retrieval can lead to either reconsolidation (accompanied or not by strengthening of the memory trace) or extinction. Here, we show that non-reinforced retrieval of inhibitory avoidance (IA) conditioning can induce memory strengthening assessed in a subsequent retention test trial. Infusion of the protein synthesis inhibitor cycloheximide or the mTOR inhibitor rapamycin into the rat basolateral complex of the amygdala (BLA) after a reactivation (retrieval) session impaired retrieval-induced strengthening.

Analysis of adhesions resulted from mesh fixation with fibrin sealant and suture: experimental intraperitoneal model.

Objective: To compare surgical fixation of polypropylene mesh (PP) and coated polypropylene mesh (PCD) using polypropylene suture and fibrin glue, as for the formation of intraperitoneal adhesions.

Methods: A sample of 46 female Wistar rats were randomized into six groups: two control groups, with five rats each, were subjected to one medial incision (MI) and the other to a U-shaped incision (UI), none of these groups received the mesh. Two groups of PP mesh, with ten rats, fixed with suture (PPF), the other with six rats, fixed with biological glue (PPC).

Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target.

Neuropeptides acting on specific cell membrane receptors of the G protein-coupled receptor (GPCR) superfamily regulate a range of important aspects of nervous and neuroendocrine function. Gastrin-releasing peptide (GRP) is a mammalian neuropeptide that binds to the GRP receptor (GRPR, BB2). Increasing evidence indicates that GRPR-mediated signaling in the central nervous system (CNS) plays an important role in regulating brain function, including aspects related to emotional responses, social interaction, memory, and feeding behavior.

Impairment of object recognition memory by rapamycin inhibition of mTOR in the amygdala or hippocampus around the time of learning or reactivation.

The role of the basolateral complex of the amygdala (BLA) in recognition memory remains poorly understood. The mammalian target of rapamycin (mTOR) in the BLA and other brain areas has been implicated in synaptic plasticity and memory. We have recently shown that mTOR signaling in both the BLA and the dorsal hippocampus (DH) is required for formation and reconsolidation of inhibitory avoidance, a fear-motivated memory task.

Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory.

Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval.

Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats.

Here we show that a systemic injection of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) ameliorated an aging-associated deficit in object recognition memory in rats when the injection was given immediately, but not 6h after training. NaB had no effect in younger rats with normal memory retention. The results indicate that HDACis can ameliorate aging-related memory impairments by influencing the early consolidation phase of memory formation.

Cognitive enhancers: focus on modulatory signaling influencing memory consolidation.

Biological research has unraveled many of the molecular and cellular mechanisms involved in the formation of long-lasting memory, providing new opportunities for the development of cognitive-enhancing drugs. Studies of drug enhancement of cognition have benefited from the use of pharmacological treatments given after learning, allowing the investigation of mechanisms regulating the consolidation phase of memory. Modulatory systems influencing consolidation processes include stress hormones and several neurotransmitter and neuropeptide systems.