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

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

作者机构：School of PharmacyAnhui University of Chinese MedicineHefei 230012China Shanghai Key Laboratory of Maternal Fetal MedicineShanghai Institute of Maternal-Fetal Medicine and Gynecologic OncologyDepartment of AnesthesiologyShanghai First Maternity and Infant HospitalTongji University School of MedicineShanghai 201204China Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Chinese Materia MedicaNanjing University of Chinese MedicineNanjing 210023China Anesthesia and Brain Function Research InstituteTongji University School of MedicineShanghai 200082China 

出 版 物：《生理学报》 (Acta Physiologica Sinica)

年 卷 期：2024年第76卷第5期

页      面：677-690页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

主　　题：antidepressant GABAa receptor positive modulator neurotransmission 

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.