基于GEO数据库挖掘与网络药理学探讨刺五加治疗阿尔茨海默病的机制

Exploring the Mechanism of Acanthopanax Senticosus in the Treatment of Alzheimer’s Disease Based on GEO Data Mining and Network Pharmacology

关键词:  刺五加  阿尔茨海默病  生物信息学  网络药理学  炎症反应

Key words:  Acanthopanax senticosus  Alzheimer’s disease  bioinformatic  network pharmacology  inflammatory response

摘要:

目的 基于生物信息学和网络药理学方法筛选刺五加治疗阿尔茨海默病(Alzheimer’s Disease，AD)的潜在药物靶点和信号通路，初步验证其药效。方法 文献检索获取刺五加成分，利用Swiss ADME对成分进行筛选，通过Swiss Target Prediction预测潜在靶点；由GSE28146数据集筛选AD差异表达基因；对刺五加靶点和AD靶点进行映射，构建“药物-成分-潜在靶点-疾病”网络及蛋白质互作网络；利用DAVID数据库进行GO和KEGG富集分析；采用Autodock软件对关键活性成分与核心靶点进行分子对接验证。采用D-半乳糖联合氯化铝诱导AD小鼠模型，Morris水迷宫试验检测各组小鼠学习记忆能力，并观察小鼠海马体的病理学变化。结果 筛选获得刺五加治疗AD活性成分24个，潜在靶点74个；“药物-成分-潜在靶点-疾病”网络提示槲皮素、山奈酚等为刺五加治疗AD的主要成分，蛋白质互作网络提示STAT3、MAPK1、PIK3CA等为关键靶点；得到GO富集条目(P<0.01)366条，KEGG富集通路(P<0.01)109条；主要涉及PI3K-AKT、AGE-RAGE和TNF等通路。分子对接结果显示，刺五加主要活性成分与主要靶点具有较好的结合活性。体内药理实验结果表明，刺五加可显著提高小鼠学习记忆能力，减轻海马组织损伤，降低海马组织中TNF-α、IL-6、IL-1β含量。结论 刺五加可能通过抑制炎症因子表达和减少炎症损伤发挥抗AD作用。

Abstract:

OBJECTIVE To screen the potential drug targets and signaling pathways of Acanthopanax senticosus for the treatment of Alzheimer’s disease(AD) by bioinformatics and network pharmacology-based approach, and to preliminarily validate its efficacy. METHODS The ingredients of Acanthopanax senticosus were obtained through literature, the ingredients were screened by Swiss ADME, and potential targets were predicted by Swiss Target Prediction. AD’s differentially expressed genes were screened from the GSE28146 dataset. The target of Acanthopanax senticosus and AD target were mapped to construct a “drug-ingredients-potential target-disease” network and protein-protein interaction network. The DAVID database was used for GO and KEGG enrichment analysis. Autodock software was used to verify the molecular docking between key active ingredients and core targets. AD mice model was induced by D-galactose combined with aluminum chloride. Morris water maze test was performed to examine the learning memory ability of each group of mice and to observe the pathological changes in the hippocampus of mice. RESULTS Screened to obtain 24 active components and 74 potential targets of Acanthopanax senticosus for the treatment of AD. “Drug-ingredients-potential target-disease” network indicated that quercetin and kaempferol were the main components of Acanthopanax senticosus for the treatment of AD, and the protein-protein interaction network indicated that STAT3, MAPK1 and PIK3CA were the key targets. Obtained 366 GO enrichment entries(P<0.01) and 109 KEGG enrichment pathways(P<0.01). It mainly involved PI3K-AKT, AGE-RAGE, TNF and other pathways. The molecular docking results showed that the main active ingredients of Acanthopanax senticosus were able to bind well to the main targets. The in vivo pharmacological results showed that Acanthopanax senticosus could significantly improve the learning and memory ability of mice, reduce hippocampal tissue damage, and decrease the content of TNF-α, IL-6, and IL-1β in hippocampal tissue. CONCLUSION Acanthopanax senticosus may exert anti-AD effects by inhibiting the expression of inflammatory factors and reducing inflammatory damage.