A novel positive modulator of GABA_A receptor exhibiting antidepressive properties.

Q3 Medicine

生理学报 Pub Date : 2024-10-25

Yin-Li Zheng, Fu-Yi Shen, Yang Wang, Jing-Pei Pan, Xian Wang, Tian-Yu Li, Wei-Jia Du, Zhi-Qiang Liu, Yang Li, Fei Guo

{"title":"A novel positive modulator of GABAA receptor exhibiting antidepressive properties.","authors":"Yin-Li Zheng, Fu-Yi Shen, Yang Wang, Jing-Pei Pan, Xian Wang, Tian-Yu Li, Wei-Jia Du, Zhi-Qiang Liu, Yang Li, Fei Guo","doi":"","DOIUrl":null,"url":null,"abstract":"γ-Aminobutyric acid (GABA) neurotransmission alterations have been implicated to play a role in depression pathogenesis. While GABAA 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 GABAA 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.","PeriodicalId":7134,"journal":{"name":"生理学报","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"生理学报","FirstCategoryId":"1087","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}

引用次数: 0

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 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.

本刊更多论文

一种新型 GABAA 受体正向调节剂，具有抗抑郁特性。

γ-氨基丁酸（GABA）神经递质的改变被认为是抑郁症发病机制中的一个环节。虽然 GABAA 受体正异位调节剂在临床实践中大有可为，但其确切的抗抑郁机制仍有待进一步阐明。本研究的目的是探讨LY-02（一种从替莫皂甙代谢产物中提取的新型化合物）对动物抑郁症的影响及其机制。行为测试结果表明，LY-02对雄性C57BL/6小鼠和Sprague Dawley（SD）大鼠均有较好的抗抑郁作用。细胞电压钳实验结果表明，LY-02能增强表达重组α6β3δ亚基GABAA受体的HEK293T细胞中GABA介导的电流。脑片的电生理记录显示，LY-02能降低C57BL/6小鼠内侧前额叶皮层（mPFC）锥体神经元的自发抑制性突触后电流（sIPSC）的振幅并增加其动作电位。Western印迹结果显示，LY-02剂量依赖性地上调了小鼠mPFC中脑源性神经营养因子（BDNF）、肌球蛋白相关激酶B（TrkB）和突触后密度蛋白95（PSD-95）的蛋白表达水平。上述结果表明，LY-02 作为 GABAA 受体的正向调节剂，可减少锥体神经元的抑制性神经传递。它还能进一步激活 BDNF/TrkB 信号通路，从而发挥抗抑郁作用。这表明 LY-02 是一种潜在的新型抑郁症治疗药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

生理学报 Medicine-Medicine (all)

CiteScore

1.20

自引率

0.00%

发文量

4820

期刊介绍： Acta Physiologica Sinica (APS) is sponsored by the Chinese Association for Physiological Sciences and Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences (CAS), and is published bimonthly by the Science Press, China. APS publishes original research articles in the field of physiology as well as research contributions from other biomedical disciplines and proceedings of conferences and symposia of physiological sciences. Besides “Original Research Articles”, the journal also provides columns as “Brief Review”, “Rapid Communication”, “Experimental Technique”, and “Letter to the Editor”. Articles are published in either Chinese or English according to authors’ submission.