케타민의 항우울제 작용에 대한 분자기전

Abstract

Previous studies have shown that ketamine produces fast antidepressant-like effects in rodent model of depression, although the molecular mechanisms underlying these behavioral effects remain incomplete. Ketamine treatment produced increase in the numbers of 5-bromo-2-deoxyuridine (BrdU) positive cells and vascular endothelial growth factor (VEGF) expression after 24 h, but not 28 d, in the hippocampal dentate gyrus (DG) after treatment completion. The viral-mediated hippocampal knockdown of VEGF produced depression-like behaviors and reduced neurogenesis, which was recovered by ketamine treatment. In addition, the investigated whether histone deacetylase 5 (HDAC5) is involved in the actions of ketamine at the levels of gene expression and antidepressant-like behaviors. Ketamine rapidly stimulates HDAC5 phosphorylation in rat hippocampal neurons. Consequently, ketamine enhanced the myocyte enhancer factor-2 (MEF2) transcriptional activity, which leads to MEF2-target gene expression. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked the antidepressant actions of ketamine both in non-stressed and Chronic Unpredictable Stress (CUS) animals. There results reveal that ketamine-induced antidepressant-like effects in rodent models of depression are mediated by regulation of HDAC5 via phosphorylation at Ser259/498, and suggest that HDAC5 could be a potential role underlying the therapeutic actions of ketamine. Characterization of these actions of ketamine including the molecular pathways that stimulate VEGF and HDAC5 phosphorylation, consistent with the rapid induction of antidepressant-like behaviors by ketamine, will provide new strategies for antidepressant drug development.