快速起效抗抑郁药研发策略:单胺(5-HT)-非单胺(Glu/GABA)长反馈神经环路候选假说的提出

被引：37

作者：

李云峰

机构：

[1] 军事科学院军事医学研究院毒物药物研究所,抗毒药物与毒理学国家重点实验室,神经精神药理学北京市重点实验室

来源：

中国药理学与毒理学杂志 | 2019年 / 33卷 / 03期

关键词：

抗抑郁药; 抑郁症; 5-羟色胺; 氯胺酮; 受体,5-HT1A; 羟哌吡酮; 18 ku转位蛋白; 受体,N-甲基-D-天冬氨酸; 受体,γ-氨基丁酸A;

D O I：

暂无

中图分类号：

R971 [神经系统药物];

学科分类号：

100115 [医学神经生物学];

摘要：

抑郁症已成为全球性严重的公共卫生问题,目前临床一线抗抑郁剂大多是基于经典的"单胺假说（策略）"研发的,这些药物普遍存在起效缓慢、有效率不高、损伤认知和致自杀倾向等缺陷,因此,突破经典单胺策略框架,发展快速起效、兼可增强认知和低毒副作用抗抑郁药物是目前全球性重大需求和方向。2019年,S-氯胺酮和别孕烯醇酮（brexanolone）等快速起效抗抑郁药的上市为基于N-甲基-D-天冬氨酸（NMDA）和γ-氨基丁酸A（GABAA）等受体的非单胺策略开辟了全新的前景。目前快速起效抗抑郁药研发总体趋势主要有二:即基于优化多靶标的单胺策略（现代单胺策略）和基于谷氨酸（Glu）-GABA平衡调控的非单胺策略。根据本实验室和国外同行的研究,我们提出单胺-非单胺即"5-羟色胺（5-HT）-Glu/GABA长反馈神经环路"候选假说,认为脑内单胺调控机制（如5-HT神经元,位于中缝核）与非单胺调节机制（Glu/GABA神经元,位于前额皮质等脑区）均是快速起效抗抑郁药机制的一部分,二者共同组成长反馈神经环路,介导前额皮质和海马等效应脑区快速增强的突触可塑性。基于该环路提出5个方面抗抑郁快速起效的候选策略:①通过解除GABA中间神经元对Glu锥体神经元的抑制或直接激活Glu锥体神经元,实现快速兴奋/抑制（E/I）平衡;②借助5-HT1A等受体同时调控5-HT神经元活性和兴奋/抑制平衡（同时增强单胺-非单胺环节）;③直接激活哺乳动物西罗莫司（雷帕霉素）靶蛋白复合物1（mTORC1）,快速增强脑源性神经营养因子（BDNF）-mTOR通路;④刺激脑内BDNF的快速释放。⑤正向变构调节GABAA受体。希望这些思路和策略为进一步发现快速抗抑郁候选靶标提供有益的借鉴。

引用

页码：161 / 173

页数：13

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