Xiao-Chai-Hu-Tang Ameliorates Depressive Symptoms via Modulating Neuro-Endocrine Network in Chronic Unpredictable Mild Stress-Induced Mice

IF 5 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2025-02-21 DOI:10.1111/cns.70290

Ying Feng, Wenkai Wang, Yingru Zhang, Yuanyuan Feng, Yiyang Zhao, Zhaozhou Zhang, Yan Wang

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Abstract

Objective

Xiao-Chai-Hu-Tang (XCHT) has been demonstrated to exert an antidepressant effect during long-term clinical practices. However, the potential mechanisms of XCHT remain unknown. This study aims to investigate the effect of XCHT on chronic unpredictable mild stress-induced mice with depressive-like behaviors and to explore the underlying mechanisms.

Methods

The active compositions and potential related targets of XCHT in the brain were obtained through UPLC-Q-TOF-MS, network pharmacology, and bioinformatics analyses, verified by experimental validation. Then, the protein–protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and molecular docking were used to predict the core targets and mechanisms of XCHT on depression. After being treated with XCHT standard decoction, based on enzyme-linked immunosorbent assay (ELISA), non-targeted metabolism, targeted LC–MS analyses, RNA-seq, quantitative RT-PCR, immunofluorescence, and western blotting were determined to clarify the mechanism of XCHT in the treatment of anxiety and depression disorder.

Results

In total, 166 active ingredients and 525 related targets of XCHT were detected and selected from the network databases. The inflammatory response and metabolism of neurotransmitters were the main related signaling pathways predicted by KEGG enrichment analyses. Behavioral testing shows that XCHT has antidepressant effects, and untargeted metabolomic studies showed it significantly reduced levels of the neurotoxic substance quinoline acid. Combining the results of molecular docking, RNA-seq, and western blot revealed that XCHT regulated nerve regeneration via BDNF/TrkB/CREB and PI3K/AKT signaling pathways. Immunofluorescence analysis revealed that XCHT downregulated the chronic stress-induced activation of microglia and astrocytes in the hippocampus.

Conclusion

XCHT exerts antidepressant functions by modulating neuroinflammation and neuroregeneration.

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小柴护汤通过调节神经内分泌网络改善慢性不可预测轻度应激小鼠抑郁症状

目的经长期临床实践证实，小柴护汤具有抗抑郁作用。然而，XCHT的潜在机制尚不清楚。本研究旨在探讨XCHT对慢性不可预测轻度应激诱导小鼠抑郁样行为的影响，并探讨其潜在机制。方法采用UPLC-Q-TOF-MS、网络药理学、生物信息学等方法，获得XCHT在脑内的有效成分和潜在相关靶点，并进行实验验证。然后，利用蛋白-蛋白相互作用（PPI）、基因本体（GO）、京都基因与基因组百科全书（KEGG）分析和分子对接等方法预测XCHT治疗抑郁症的核心靶点和机制。经XCHT标准汤治疗后，通过酶联免疫吸附试验（ELISA）、非靶向代谢、靶向LC-MS分析、RNA-seq、定量RT-PCR、免疫荧光、western blotting等方法，明确XCHT治疗焦虑抑郁障碍的作用机制。结果从网络数据库中共筛选出XCHT的166种有效成分和525种相关靶点。炎症反应和神经递质代谢是KEGG富集分析预测的主要相关信号通路。行为测试表明XCHT具有抗抑郁作用，非靶向代谢组学研究表明它显著降低了神经毒性物质喹啉酸的水平。结合分子对接、RNA-seq和western blot结果发现，XCHT通过BDNF/TrkB/CREB和PI3K/AKT信号通路调控神经再生。免疫荧光分析显示，XCHT下调慢性应激诱导的海马小胶质细胞和星形胶质细胞的激活。结论XCHT通过调节神经炎症和神经再生发挥抗抑郁作用。

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公司名称

产品信息

陶术

protease inhibitor

陶术

phosphatase inhibitor

来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.