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一种具有抗抑郁特性的GABA_A受体新型正调节剂

郑银丽^1,*, 沈富毅², 汪洋³, 潘茎沛⁴, 王贤⁵, 李天宇^2,4,6, 杜唯佳², 刘志强^2,4,6, 李扬^1,4, 郭飞^1,4

¹安徽中医药大学药学院，合肥 230012；²上海市母胎医学重点实验室，上海市母胎医学与妇科肿瘤研究所，上海市第一妇婴保健院麻醉科，同济大学医学院，上海 201204；³沈阳药科大学无涯创新学院，沈阳 110016；⁴中国科学院上海药物研究所药物研究国家重点实验室，上海 20120；⁵南京中医药大学中药学院，南京 210023；⁶同济大学医学院麻醉与脑功能研究所，上海 200082

摘要

γ-氨基丁酸(γ-aminobutyric acid, GABA)神经递质传递的失调是抑郁症发病的重要机制。虽然临床试验表明GABA_A受体正变构调节剂有积极的抗抑郁作用，但其确切的抗抑郁机制仍有待进一步阐明。本研究旨在探讨一种来源于知母皂苷代谢物的新型化合物LY-02对动物抑郁的作用及其机制。行为学试验结果显示，LY-02在雄性C57BL/6小鼠和Sprague Dawley (SD)大鼠体内均表现较好的抗抑郁效果。细胞电压钳实验结果显示，LY-02增强表达含重组α6β3δ亚基的GABA_A受体的HEK293T细胞GABA所介导的电流；脑切片电生理记录显示，LY-02降低C57BL/6小鼠内侧前额叶皮层(medial prefrontal cortex, mPFC)锥体神经元自发抑制性突触后电流(spontaneous inhibitory postsynaptic current, sIPSC)振幅，并增加其动作电位。Western blot结果显示，LY-02剂量依赖性上调小鼠mPFC脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)、原肌球蛋白相关激酶B (tropomyosin related kinase B, TrkB)和突触后密度蛋白-95 (postsynaptic density protein 95, PSD-95)蛋白表达水平。以上结果提示，LY-02作为GABA_A受体的正向调节剂，可减少锥体神经元的抑制性神经递质，进一步激活BDNF/TrkB信号通路，从而发挥抗抑郁作用，表明LY-02是一种潜在的新型抑郁症治疗药物。

关键词： 抗抑郁药物; GABAA受体; 正调节剂; 神经传递

A novel positive modulator of GABA_A receptor exhibiting antidepressive properties

ZHENG Yin-Li^1,*, SHEN Fu-Yi², WANG Yang³, PAN Jing-Pei⁴, WANG Xian⁵, LI Tian-Yu^2,4,6, DU Wei-Jia², LIU Zhi-Qiang^2,4,6, LI Yang^1,4, GUO Fei^1,4

¹School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China；²Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China；³Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China；⁴State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China；⁵School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China；⁶Anesthesia and Brain Function Research Institute, Tongji University School of Medicine, Shanghai 200082, China

Abstract

γ-Aminobutyric acid (GABA) neurotransmission alterations have been implicated to play a role in depression pathogenesis. While GABA_A receptor positive allosteric modulators are emerging as promising in clinical practice, their precise antidepressant mechanism remains to be further elucidated. The aim of the present study was to investigate the effects of LY-02, a novel compound derived from the metabolite of timosaponin, on depression in animals and its mechanism. The results of behavioral tests showed that LY-02 exhibited better antidepressant effects in both male C57BL/6 mice and Sprague Dawley (SD) rats. The results of cellular voltage clamp experiments showed that LY-02 enhanced GABA-mediated currents in HEK293T cells expressing recombinant α6β3δ subunit- containing GABA_A receptors. Electrophysiological recording from brain slices showed that LY-02 decreased the amplitude of spontaneous inhibitory postsynaptic current (sIPSC) and increased action potentials of pyramidal neurons in the medial prefrontal cortex (mPFC) of C57BL/6 mice. Western blot results showed that LY-02 dose-dependently up-regulated the protein expression levels of brain-derived neurotrophic factor (BDNF), tropomyosin related kinase B (TrkB) and postsynaptic density protein 95 (PSD-95) in mPFC of mice. The above results suggest that LY-02, as a positive modulator of GABAA receptors, reduces inhibitory neurotransmission in pyramidal neurons. It further activates the BDNF/TrkB signaling pathway, thus exerting antidepressant effects. It suggests that LY-02 is a potential novel therapeutic agent for depression treatment.

Key words: antidepressant; GABAA receptor; positive modulator; neurotransmission

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引用本文：

郑银丽, 沈富毅, 汪洋, 潘茎沛, 王贤, 李天宇, 杜唯佳, 刘志强, 李扬, 郭飞. 一种具有抗抑郁特性的GABA_A受体新型正调节剂[J]. 生理学报 2024; 76 (5): 677-690.

ZHENG Yin-Li, SHEN Fu-Yi, WANG Yang, PAN Jing-Pei, WANG Xian, LI Tian-Yu, DU Wei-Jia, LIU Zhi-Qiang, LI Yang, GUO Fei. A novel positive modulator of GABA_A receptor exhibiting antidepressive properties. Acta Physiol Sin 2024; 76 (5): 677-690