A comprehensive pharmacology study reveals the molecular mechanisms underlying the antidepressant effects of Gastrodiae Rhizoma

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-04-19 DOI:10.1016/j.phymed.2025.156761

Pei Liu , Zhihuang Zhao , Haili Zhang , Chenghong Xiao , Meidan Wang , Chengyan Yang , Yu-e Liu , Lulu Wang , Hui He , Yangyan Ge , Yan Fu , Tao Zhou , Zili You , Jinqiang Zhang

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Abstract

Background

Gastrodiae Rhizoma (GR) and its extract have been widely used in the treatment of depression, but the underlying mechanism of its antidepressant effects is unclear due to its numerous components.

Purpose

Revealing the cellular and molecular mechanisms underlying the antidepressant effects of GR through a comprehensive pharmacology-based in vivo and in vitro investigation.

Methods

A mouse model of depression was established using chronic mild stress (CMS) procedure, and the antidepressant effects of GR were evaluated using systematic behavior. Metabolites in GR decoction and in mouse brain were identified by UPLC-QTOF-MS technology. Core components and targets of GR against MDD were screened based on network pharmacology analysis and molecular docking. The mechanism through which GR mitigated MDD was explored using transcriptome analysis, immunohistochemistry and western blotting in vitro and in vivo.

Results

A total of 273 components were identified in the GR decoction, out of which 15 were detected in the brain of depressed mice treated with the GR decoction. We further identified nine key active ingredients, six essential targets, and fifth signaling pathways associated with the therapeutic effects of GR against MDD. We confirmed that the active ingredients of GR can target the neural stem/precursor cells (NSPCs) in the hippocampus of depressed mice to promote neurogenesis, as evidenced by a significant increase in the numbers of DCX⁺ cells, BrdU⁺ cells, BrdU⁺-DCX⁺ cells, and BrdU⁺-NeuN⁺ cells within the hippocampus of GR-treated mice compared to salinetreated mice under CMS exposure. Moreover, we have identified that the key active constituents of GR, namely gastrodin and parishin C, exert a targeted effect on EGFR to activate PI3K-Akt signaling in NSPCs, thereby facilitating proliferation and differentiation of NSPCs.

Conclusion

The antidepressant effect of GR involves the facilitation of PI3K/Akt-mediated neurogenesis through gastrodin and parishin C targeting EGFR in NSPCs.

Abstract Image

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全面的药理学研究揭示了天麻抗抑郁作用的分子机制

黄芪及其提取物已被广泛用于抑郁症的治疗，但由于其成分众多，其抗抑郁作用的机制尚不清楚。目的通过全面的体内和体外药理学研究，揭示GR抗抑郁作用的细胞和分子机制。方法采用慢性轻度应激法（CMS）建立抑郁小鼠模型，采用系统行为法评价GR的抗抑郁作用。采用UPLC-QTOF-MS技术对葛参汤中代谢物和小鼠脑内代谢物进行鉴定。通过网络药理学分析和分子对接，筛选GR抗MDD的核心成分和靶点。通过体外和体内转录组分析、免疫组织化学和western blotting，探讨GR减轻MDD的机制。结果黄芪汤剂中共检出273种成分，其中黄芪汤剂对抑郁症小鼠脑组织中检出15种。我们进一步确定了与GR治疗MDD相关的9个关键活性成分、6个基本靶点和5个信号通路。我们证实了GR的有效成分可以靶向抑郁小鼠海马中的神经干/前体细胞（NSPCs）促进神经发生，与盐处理小鼠相比，GR处理小鼠海马中的DCX+细胞、BrdU+细胞、BrdU+-DCX+细胞和BrdU+-NeuN+细胞的数量显著增加。此外，我们发现GR的关键活性成分天麻素和parishin C对EGFR有靶向作用，激活NSPCs中的PI3K-Akt信号，从而促进NSPCs的增殖和分化。结论GR的抗抑郁作用与通过天麻素和parishin C靶向EGFR促进PI3K/ akt介导的NSPCs神经发生有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.