糖原合成酶激酶3β在阿姆西汀抗抑郁中的作用及其机理研究

Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β (GSK3β) action played an important role in depression pathogenesis. Our previous study found that ammuxetine, a novel serotonin and norepinephrine inhibitor, displayed antidepressant activity more potent and faster than existing antidepressants, which may be due to the upregulation of hippocampal pGSK3β and the enhancement of neural plasticity and neurogenesis. With application of various methods including behavioral pharmacology, molecular biology, and neurobiology, the present study investigates the molecular mechanism underlying the antidepressant effect of ammuxetine, focusing on GSK3β and its important the role in neural plasticity and neurogenesis, and three important questions are expected to be answered: ① Does the up-regulation of GSK3β phosphorylation paly a key role in the antidepressant action of ammuxetine? ② Which signaling pathway induce the phosphorylation of GSK3β, PI3K pathway or Wnt pathway? ③ Does GSK3β exert this effect by regulating neural plasticity and neurogenesis? The present study is expected to clarify the key signaling molecules and related signal transduction mechanism, which may provide experimental support for the development of ammuxetine with independent intellectual property. Additionally, it is expected that this study could provide novel exploration for discovering the mechanism underlying the therapeutic action of antidepressants.

近年来研究发现，糖原合成酶激酶3β（GSK3β)过度激活（磷酸化水平降低）与抑郁症发生密切相关。本课题前期研究发现阿姆西汀具有强效、速效抗抑郁作用，并可逆转抑郁模型大鼠pGSK3β表达降低，具有促神经元再生和神经可塑性的作用。本研究在前期工作的基础上，以GSK3β为切入点，围绕其在神经可塑性和神经元再生中的重要作用，通过行为药理学、分子生物学、神经生物学等多种手段，探讨阿姆西汀速效、强效抗抑郁作用的精细分子机制，重点回答以下三个问题：①促进GSK3β磷酸化是否是阿姆西汀抗抑郁作用的关键环节？②GSK3β磷酸化是由PI3K通路还是Wnt通路激活所诱导？③GSK3β是否通过调节神经可塑性和神经元再生参与阿姆西汀的抗抑郁作用？本研究的开展希望能够阐明阿姆西汀抗抑郁作用的细胞内关键信号分子和转导机制，为其发展成为具有自主知识产权的Ⅰ类新药提供实验依据，并为深入研究抗抑郁药的分子机制提供新的思路。

该项目以GSK3β为切入点，通过行为药理学、分子生物学、神经生物学等多种手段，初步阐明了阿姆西汀抗抑郁作用与抑制GSK3β功能（促进GSK3β磷酸化）之间的关系，主要研究发现包括：1)阿姆西汀可逆转抑郁模型动物海马pGSK3β表达降低，该发现在多种抑郁模型中得到了相互验证；2)PI3K/AKT/GSK3β信号通路的激活是阿姆西汀发挥抗抑郁作用所必需，而Wnt信号通路仅部分参与了阿姆西汀抗抑郁作用的发挥；3)无论采用化学抑制剂还是分子生物学技术阻断GSK3β磷酸化，均可阻断阿姆西汀的抗抑郁作用，并可同时阻断阿姆西汀对PI3K/AKT通路的激活以及促进BDNF表达的作用。该项目阐明了阿姆西汀抗抑郁作用的细胞内关键信号分子和信号转导机制，为其发展成为具有自主知识产权的Ⅰ类新药提供实验依据，并为深入研究抑郁症的发生和SNRIs抗抑郁作用的分子机制研究提供新的思路。本研究成果发表SCI论文3篇、国内核心期刊论文3篇、会议论文2篇，获得日本和印度发明专利各1项，培养毕业博士研究生1名、硕士研究生4名。参加国内学术交流2次，作青年英文汇报1次，获墙报交流一等奖1次。