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

Strategy for development of fast-onset antidepressive agents: candidate hypothesis of monoamine(5-HT)-nonmonoamine(Glu/GABA) long-feedback neural circuit

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。

Depression has become a serious global public health concern. Almost all the current first- line antidepressants developed are based on the classical "monoamine hypothesis (strategy)". These drugs commonly possess a series of defects, including slow-onset, lower response, cognitive injury and suicidal tendencies. So, by breaking through the classical monoamine strategy framework, developing new antidepressants with fast-onset, cognitive-enhancement and less adverse reactions is a major global demand. In 2019, fast-onset antidepressants S-ketamine(S-Ket) and brexanolone were approved by the FDA of USA, which opened up a new field for the non-monoamine strategy mainly based on the N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid A (GABAA) receptors. There are currently two main trends in the research and development of rapid onset antidepressants: the optimized multi-target monoamine strategy (modern monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance regulation. According to the research of our laboratory and foreign colleagues, we propose a candidate hypothesis of the "monoamine (5-HT)-nonmonoamine (Glu/GABA) long feedback neural circuit". It is believed that both monoamine regulatory mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoamine regulatory mechanisms (Glu/GABA neurons located in the prefrontal cortex and other brain regions) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long-feedback neural loop mediating the fast synaptogenesis of the brain regions including the prefrontal cortex and hippocampus. Based on this hypothesis, we propose five candidate strategies for rapid onset of antidepressant development.① By relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating glutamatergic pyramidal neurons, the rapid excitation/inhibition (E/I) balance can be achieved;② simultaneous regulation of 5-HT neuronal activity and E/I balance by 5-HT transporter and 5-HT receptors such as 5-HT1A (that means simultaneous enhancement of monoamine and nonmonoamine links);③ direct activation of mammalian sirolimus (rapamycin) target protein complex 1 (mTORC1) and rapid enhance ment of the brain- derived neurotrophic factor (BDNF)- mTOR signaling;④ stimulation of the fast release of BDNF in the brain;⑤ positive allosteric modulator of GABAA receptor. We hope that these ideas and strategies will bring about a breakthrough for the development of a new generation of antidepressants in China in the future, and provide useful reference for further discovery of candidate targets for rapid antidepressant therapy.