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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Ethnopharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1389768

Activation of GABA type A receptor is involved in the anti-insomnia effect of Huanglian Wendan Decoction

Provisionally accepted
Fuyun Tian Fuyun Tian 1*Liang Li Liang Li 2Xiaorong Wu Xiaorong Wu 2Jili Gong Jili Gong 1Zhuqiang Wang Zhuqiang Wang 2Weibo Dai Weibo Dai 2Li Qiu Li Qiu 1Hongyuan Zuo Hongyuan Zuo 1Mengqin Yi Mengqin Yi 1Hui Yuan Hui Yuan 1Mei Hu Mei Hu 2Zhaobing Gao Zhaobing Gao 1
  • 1 Zhongshan Institute for Drug Discovery, Zhongshan, China
  • 2 Zhongshan Traditional Chinese Medicine Hospital, Zhongshan, China

The final, formatted version of the article will be published soon.

    Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) prescribed to patients diagnosed with insomnia, which can achieve excellent therapeutic outcomes. As positively modulating the γ-aminobutyric acid (GABA) type A receptors (GABAARs) is the most effective strategy to manage insomnia, this study aimed to investigate whether the activation of GABAARs is involved in the anti-insomnia effect of HWD. We assessed the metabolites of HWD using LC/MS and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and tested the pharmacological activity in vitro and in vivo using whole-cell patch clamp and insomnia zebrafish model. In HEK293 cells expressing α1β3γ2L GABAARs, HWD effectively increased the GABA-induced currents and could induce GABAAR-mediated currents independent of the application of GABA. In the LC-MS (QToF) assay, 31 metabolites were discovered in negative ion modes and 37 metabolites were found in positive ion modes, but neither three selected active metabolites, Danshensu, Coptisine, or Dihydromyricetin, showed potentiating effects on GABA currents. 62 active metabolites of the seven botanical drugs were collected based on the TCMSP database and 19 of them were selected for patch-clamp verification according to the virtual docking simulations and other parameters. At a concentration of 100 μM, GABA-induced currents were increased by (+)-Cuparene (278.80 ± 19.13 %), Ethyl glucoside (225.40 ± 21.77 %), and β-Caryophyllene (290.11 ± 17.71 %). In addition, (+)-Cuparene, Ethyl glucoside, and β-Caryophyllene could also serve as positive allosteric modulators (PAMs) and shifted the GABA dose-response curve (DRC) leftward significantly. In the PCPA-induced zebrafish model, Ethyl glucoside showed anti-insomnia effects at concentrations of 100 μM. In this research, we demonstrated that the activation of GABAARs was involved in the anti-insomnia effect of HWD, and Ethyl glucoside might be a key metabolite in treating insomnia.

    Keywords: Huanglian Wendan Decoction (HWD), GABA A type receptor (GABAARs), insomnia, Zebrafish, TCMSP, Traditional Chinese Medicine Systems Pharmacology

    Received: 22 Feb 2024; Accepted: 01 May 2024.

    Copyright: © 2024 Tian, Li, Wu, Gong, Wang, Dai, Qiu, Zuo, Yi, Yuan, Hu and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Fuyun Tian, Zhongshan Institute for Drug Discovery, Zhongshan, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.