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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

Received: 　　Accepted:

Corresponding author: 郑银丽　　E-mail:

Citing This Article：

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