cp-154526 and Memory-Disorders

Accumulating evidences demonstrated that early postnatal maternal separation induced remarkable social and memory defects in the adult rodents. Early-life stress induced long-lasting functional adaptation of neuroendocrine hypothalamic-pituitary-adrenal axis, including neuropeptide corticotrophin-releasing hormone (CRH) in the brain. In the present study, a significantly increased hippocampal CRH was observed in the adult rats with postnatal maternal separation, and blockade of CRHR1 signaling significantly attenuated the hippocampal synaptic dysfunction and memory defects in the modeled rats. Postnatal maternal separation enduringly increased histone H3 acetylation and decreased cytosine methylation in Crh promoter region, resulting from the functional adaptation of several transcriptional factors, in the hippocampal CA1 of the modeled rats. Enriched environment reversed the epigenetic upregulation of CRH, and ameliorated the hippocampal synaptic dysfunction and memory defects in the adult rats with postnatal maternal separation. This study provided novel insights into the epigenetic mechanism underlying postnatal maternal separation-induced memory deficiency, and suggested environment enrichment as a potential approach for the treatment of this disorder.

Topics: Acetylation; Animals; Animals, Newborn; Corticotropin-Releasing Hormone; Electric Stimulation; Epigenesis, Genetic; Hippocampus; Histones; Long-Term Potentiation; Maternal Deprivation; Maze Learning; Memory Disorders; Methyl-CpG-Binding Protein 2; Neuronal Plasticity; Phosphorylation; Promoter Regions, Genetic; Pyrimidines; Pyrroles; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Up-Regulation

Corticotropin-releasing hormone (CRH) has been implicated in ischemia-induced neurotoxicity, due in part to excitatory effects at the hippocampus, and the demonstrated neuroprotective effects of centrally administered, non-specific CRH antagonists. However, a number of issues remain to be clarified from these studies, including the relative contribution of CRH receptor subtypes, and the efficacy of these compounds to alter ischemia-induced behavioral impairments. In the current study, a highly selective, systemically administered CRH1 antagonist (CP154,526) failed to reverse global ischemia-induced cell death in hippocampal CA1 neurons or spatial memory impairments as assessed in the radial arm maze. Similarly, central administration of alpha-helical CRH failed to confer protection against ischemic damage. Interestingly, CRH1 antagonism reversed ischemia-induced hyperactivity in a novel open field, suggesting that modulation of this behavior is independent of effects on hippocampal CA1 cell loss. Failure of the current study to demonstrate neuroprotective effects of either the selective or non-selective CRH antagonists tested challenges the proposed neurotoxic role of CRH in global ischemia. These findings are discussed in relationship to recent findings reconsidering the participation of CRH in excitotoxic-mediated cellular damage.

Topics: Animals; Behavior, Animal; Cell Count; Dose-Response Relationship, Drug; Exploratory Behavior; Hippocampus; Ischemia; Male; Memory Disorders; Nerve Degeneration; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Spatial Behavior; Time Factors