A novel positive modulator of GABA_(A) receptor exhibiting antidepressive properties  

一种具有抗抑郁特性的GABA_(A)受体新型正调节剂

作　　者：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 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(安徽中医药大学药学院,合肥230012;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;沈阳药科大学无涯创新学院,沈阳110016;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201203;南京中医药大学中药学院,南京210023;同济大学医学院麻醉与脑功能研究所,上海200082)

机构地区：[1]School of Pharmacy,Anhui University of Chinese Medicine,Hefei 230012,China [2]Shanghai 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 [3]Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China [4]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [5]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China [6]Anesthesia and Brain Function Research Institute,Tongji University School of Medicine,Shanghai 200082,China

出　　处：《生理学报》2024年第5期677-690,共14页Acta Physiologica Sinica

摘　　要：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 subunitcontaining 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 m PFC of mice. The above results suggest that LY-02, as a positive modulator of GABA_(A) 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.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,m PFC)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：ANTIDEPRESSANT GABAa receptor positive modulator NEUROTRANSMISSION 

分 类 号：R971.43[医药卫生—药品]