ANA-12与7, 8-DHF在不同神经环路抗抑郁作用的神经可塑性机制研究

项目名称： ANA-12与7, 8-DHF在不同神经环路抗抑郁作用的神经可塑性机制研究

项目编号： No.81471374

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马现仓

作者单位： 西安交通大学

项目金额： 70万元

中文摘要： 重性抑郁障碍（MDD）病因和发病机制目前仍不完全清楚。研究表明脑源性神经营养因子（BDNF）及其受体TrkB已被作为MDD病理生理的关键中介因子。已有文献及本课题小组的预实验发现新近报导的TrkB受体拮抗剂ANA-12与TrkB受体激动剂7,8-DHF均具有抗抑郁作用，但其内在的机制尚不清楚。本研究正是从这一表面矛盾的结果出发，提出理论假设:MDD的不同神经环路（VTA-NAc、海马-PFC）上BDNF受体拮抗剂和受体激动剂的神经可塑性改变（突触可塑性、神经发生、结构可塑性、神经可塑性分子表达及其信号通路等）不同。本研究采用本课题小组已经成功建立的最接近临床真实的不可预期慢性温和应激（UCMS）小鼠抑郁模型对这一假说进行验证，并对比传统抗抑郁剂丙咪嗪和氟西汀，以期从神经环路角度寻求MDD发病机制的新突破。

中文关键词： 重性抑郁障碍；神经环路；神经可塑性；ANA-12；7；；8-DHF

英文摘要： Major depressive disorder (MDD) is a common, recurrent mental illness that affects millions of people worldwide. Accumulating evidence suggests that the neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathogenesis and treatment of this disease. Our preliminary studies showed both TrkB antagonist ANA-12 and TrkB agonist 7, 8- dihydroxyflavone (7, 8-DHF), two novel therapeutic compounds, exerted antidepressant effects. Based on this contradiction, we hypothesized the changes of neural plasticity on different neural circuits (VTA-NAc/hippocampus-PFC) induced by ANA-12 and 7, 8-DHF respectively are different. In order to test our hypothesis, we will carry out experiments on unpredictable chronic mild stress (UCMS) mice model with ANA-12, 7, 8-DHF, and traditional antidepressants imipramine, fluoxetine. We hope this study will benefit unravelling the pathophysiology of MDD, and also provide a promising path to develop new antidepressants.

英文关键词： major depressive disorder;neural circuits;neural plasticity;ANA-12;7; 8-DHF