基于网络药理学的补阳还五汤治疗阿尔兹海默症的作用机制研究

Mechanism of Buyang Huanwu Decoction in the Treatment of Alzheimer′s disease Based on Network Pharmacology

目的:运用网络药理学的研究方法,初步探讨补阳还五汤治疗阿尔兹海默症(AD)的作用机制。方法:借助中药系统药理学数据库与分析平台(TCMSP)、OMIM、DrugBank、TTD数据库检索和收集AD的相关靶点;利用TCMSP和TCM@TAIWAN数据库检索和筛选补阳还五汤组方药物的活性成分,并通过PharmMapper服务器预测化合物潜在作用靶点;通过与收集的AD靶点比对获得活性成分作用的AD靶点,并利用STRING数据库和Cytoscape软件构建和分析AD靶点的PPI网络图和“组方药物-活性成分-AD靶点”网络图;分别通过DAVID系统、KOBAS 3.0数据库对AD靶点进行基因本体(GO)富集分析和京都基因和基因组百科全书(KEGG)通路富集分析。结果:从补阳还五汤中筛选出92个活性成分,其中来自赤芍的芍药内酯苷、4-乙基芍药苷、4-氧-甲基-芍药苷可能是重要的多效活性成分;活性成分经靶点预测和比对后确定33个抗AD靶点,其中CASP3、MAPK14、BCHE、BACE1可能是抗AD的关键靶点。活性成分通过作用上述AD靶点调控MAPK、PI3K/AKT、Rap1、Ras等信号通路,影响蛋白水解、蛋白磷酸化、雌激素应答等生物过程,抑制Aβ的生成,降低神经元炎症反应和神经细胞凋亡,减弱胆碱酯酶活性,进而达到治疗AD的目的。结论:通过网络药理学方法研究补阳还五汤治疗AD的活性成分和作用机制,揭示了补阳还五汤在治疗AD方面具有多成分、多靶点、多途径的优点,为补阳还五汤的后期实验提供新思路。

Objective:To explore the mechanism of Buyang Huanwu Decoction in the treatment of Alzheimer′s Disease(AD)with the method of network pharmacology.Methods:We retrieved and collected AD targets with the help of TCMSP,OMIM,DrugBank and TTD databases.Searched and screened the active compounds in Buyang Huanwu Decoction through the TCMSP and TCM@TAIWAN databases,and predicted potential targets of compounds through the PharmMapper server.Obtained the AD targets that interact with Buyang Huanwu Decoction by comparing with the collected AD targets.Constructing and analyzing the protein-protein interaction network of targets of Buyang Huanwu Decoction against AD and the network of“herbs-active compounds-AD targets”with STRING database and Cytoscape software separately.GO functional annotation and KEGG pathway enrichment analysis were performed on AD targets through DAVID system and KOBAS 3.0 database.Results:A total of 92 active compounds were screened from Buyang Huanwu Decoction,among which paeoniflorin,4-ethylpaeoniflorin and 4-O-methyl-paeoniflorin from the Radix Paeoniae Rubra may be the important multiple activity ingredients.After targets prediction and comparison,33 AD targets were determined,among which CASP3,MAPK14,BCHE and BACE1 may be the key targets of Buyang Huanwu Decoction against AD.The AD targets were affected by active components to regulate proteolysis,protein phosphorylation,estrogen response and other biological processes,to inhibit the production of Aβ,decrease neuronal inflammation and apoptosis of nerve cells,and reduce the activity of cholinesterase by participating in MAPK,PI3K/AKT,Rap1,Ras and other signaling pathways,to achieve the purpose of treating AD.Conclusion:Research on the active ingredients and mechanism of Buyang Huanwu Decoction in the treatment of AD through network pharmacology methods,revealing that Buyang Huanwu Decoction has the advantages of multiple components,multiple targets and multiple pathways in the treatment of AD,which provides a new idea for the later experiment of Buyang Huanwu Decoction.