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基于网络药理学和实验验证的荆芥挥发油治疗抑郁症的机制研究

[Mechanism of essential oil from Schizonepeta tenuifolia in treatment of depression based on network pharmacology and experimental verification].

作者信息

Qin Tian-Tian, Xie Hong-Xiao, Hu Jing-Wen, Zeng Jiu-Seng, Liu Rong, Zeng Nan

机构信息

State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine Chengdu 611137, China College of Pharmacy, Chengdu University of Traditional Chinese Medicine Chengdu 611137, China.

出版信息

Zhongguo Zhong Yao Za Zhi. 2023 Feb;48(4):1066-1075. doi: 10.19540/j.cnki.cjcmm.20221014.705.

DOI:10.19540/j.cnki.cjcmm.20221014.705
PMID:36872277
Abstract

This paper aimed to explore the antidepressant effect of the essential oil from Schizonepeta tenuifolia Briq.(EOST) on the treatment of depression and its mechanism by using a combination of network pharmacology and the mouse model of lipopolysaccharide(LPS)-induced depression. The chemical components in EOST were identified using gas chromatography-mass spectrometer(GC-MS), and 12 active components were selected as the study objects. The targets related to EOST were obtained by Traditional Chinese Medicines Systems Pharmacology(TCMSP) and SwissTargetPrediction database. The targets related to depression were screened out through GeneCards, Therapeutic Target Database(TTD), and Online Mendelian Inheritance in Man(OMIM) database. The Venny 2.1 was applied to screen out the common targets of EOST and depression. The targets were imported into Cytoscape 3.7.2 to generate "drug-active component-diease-target" network diagram. The protein-protein interaction(PPI) network was constructed using STRING 11.5 database and Cytoscape 3.7.2, and the core targets were screened out. DAVID 6.8 database was used for Gene Ontology(GO) func-tional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and subsequently the enrichment results were visualized through the bioinformatics platform. The mouse model of depression was induced by intraperitoneally injecting with LPS in mice. Before modeling, mice were administrated orally with EOST. The antidepressant effect of EOST was evalua-ted by tail suspension test(TST), forced swimming test(FST), and novelty suppressed feeding test(NSFT) after modeling. The content of interleukin(IL)-1β was determined by enzyme-linked immunosorbent assay(ELISA), and the protein expression levels of IL-1β and pro IL-1β in the hippocampus were determined by Western blot. There were 12 main components and 179 targets in EOAT, of which, 116 targets were related to depression, mainly involved in neuroactive ligand-receptor interaction, calcium signaling pathway, and cyclic adenosine monophosphate(cAMP) signaling pathway. Biological processes such as synaptic signal transduction, G-protein coupled receptor signaling pathway, and chemical synaptic transmission were involved. Molecular functions such as neurotransmitter receptor activity, RNA polymerase Ⅱ transcription factor activity, and heme binding were involved. In mice experiments, the results showed that EOST at 100 mg·kg(-1) and 50 mg·kg(-1) significantly shortened the immobility time in TST and FST as well as the feeding latency in NSFT compared with the model group, decreased the levels of serum IL-1β and NO, and reduced the protein expression levels of IL-1β and pro IL-1β in the hippocampus. In conclusion, EOST shows a good antidepressant effect in a multi-component, multi-target, and multi-pathway manner. The mechanism may be attributed to the fact that EOST can down-regulate the protein expression levels of IL-1β and pro IL-1β, decrease the release of inflammatory factors, and reduce neuroinflammation response.

摘要

本文旨在通过网络药理学与脂多糖(LPS)诱导的小鼠抑郁模型相结合的方法,探讨荆芥挥发油(EOST)治疗抑郁症的抗抑郁作用及其机制。采用气相色谱 - 质谱联用仪(GC - MS)鉴定EOST中的化学成分,并选取12种活性成分作为研究对象。通过中药系统药理学数据库(TCMSP)和瑞士靶点预测数据库获取与EOST相关的靶点。通过基因卡片(GeneCards)、治疗靶点数据库(TTD)和人类孟德尔遗传在线数据库(OMIM)筛选出与抑郁症相关的靶点。应用Venny 2.1筛选出EOST与抑郁症的共同靶点。将靶点导入Cytoscape 3.7.2生成“药物 - 活性成分 - 疾病 - 靶点”网络图。利用STRING 11.5数据库和Cytoscape 3.7.2构建蛋白质 - 蛋白质相互作用(PPI)网络,并筛选出核心靶点。使用DAVID 6.8数据库进行基因本体(GO)功能富集分析和京都基因与基因组百科全书(KEGG)通路富集分析,随后通过生物信息学平台对富集结果进行可视化。通过腹腔注射LPS诱导小鼠抑郁模型。在建模前,给小鼠口服EOST。建模后通过悬尾试验(TST)、强迫游泳试验(FST)和新奇抑制摄食试验(NSFT)评估EOST的抗抑郁作用。采用酶联免疫吸附测定(ELISA)法测定白细胞介素(IL)-1β的含量,通过蛋白质免疫印迹法测定海马中IL - 1β和前体IL - 1β的蛋白表达水平。EOAT中有12种主要成分和179个靶点,其中116个靶点与抑郁症相关,主要涉及神经活性配体 - 受体相互作用、钙信号通路和环磷酸腺苷(cAMP)信号通路。涉及突触信号转导、G蛋白偶联受体信号通路和化学突触传递等生物学过程。涉及神经递质受体活性、RNA聚合酶Ⅱ转录因子活性和血红素结合等分子功能。在小鼠实验中,结果表明,与模型组相比,100 mg·kg⁻¹和50 mg·kg⁻¹的EOST显著缩短了TST和FST中的不动时间以及NSFT中的摄食潜伏期,降低了血清IL - 1β和NO水平,并降低了海马中IL - 1β和前体IL - 1β的蛋白表达水平。综上所述,EOST以多成分、多靶点、多途径的方式显示出良好的抗抑郁作用。其机制可能归因于EOST可下调IL - 1β和前体IL - 1β的蛋白表达水平,减少炎症因子的释放,并减轻神经炎症反应。

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