Exploring The Potential Targets And Mechanism Of Basic TCM Compound Combined With Donepezil In The Treatment Of Alzheimer’s Disease Based On Network Pharmacology

Background: Alzheimer’s disease(AD)is a complex degenerative disease of the central nervous system,without a completely clear pathogenesis.Donepezil is a representative drug of anti-AD,and the combination of traditional Chinese medicine(TCM)compound and donepezil can improve the therapeutic effect of donepezil against AD and reduce its toxic and side effects.However,the mechanism of anti-AD based basic Chinese medicine compound(BCMC)is still unclear,provided a possible research path with network pharmacology and other methods.Objective: To explore the potential targets and molecular mechanism of BCMC combined with donepezil in the treatment of AD.Methods: The first part,searching database in English and Chinese: China National Knowledge Infrastructure(CNKI),Chinese Scientific Journals Full-Text Database(VIP),wanfang database,Pub Med,Web of Science.Retrieval period: from database construction to December 2019.Based on the basic principle of evidence-based medicine(EBM),the included articles were screened out according to the inclusion and exclusion criteria given in this paper.All Chinese herbs used in combination with donepezil for the treatment of AD in the included articles were counted.On the basis of the basic pathogenesis of BCMC,the Apriori algorithm of SPSS Modeler software was used,and the combination of anti-AD’s herbs with >1 improvement degree,high support rate and high confidence degree.The second part,the chemical components of TCM known in TCMSP platform and Chinese materia medica were retrieved as well as the structural formula of theirs active compound in Pub Chem,and then imported into Pharmmapper database to obtain drug-related targets.Further TCMSP,OMIM,TTD,Pharm Gkb,CTD,Genecard and Drug Bank databases were searched for AD-related genes.After that,the drug’s target protein were matched with the disease genes,to screen common gene targets and construct protein interaction network(PPI).Eventually this targets were analyzed topologically via Network Analyzer in Cytoscape,with using KOBAS 3.0 for GO enrichment analysis and KEGG Pathway analysis.Results: Part one: A total of 28 included articles were selected.Meta-analysis results showed that compared with donepezil alone,the combination of BCMC and donepezil in the treatment of AD could increase MMSE score,reduce ADL score and the incidence of adverseevents,with statistically significant differences.Based on data mining and the basic pathogenesis of TCM,the anti-AD basic BCMC named SYR was obtained: Acorus tatarinowii(Shichangpu),Polygala(Yuanzhi)and Cistanche(Roucongrong).Part two: 41 matched targets of SYR and AD were obtained.The network analysis results showed that the target involved 13 active components in SYR.The GO enrichment analysis results showed that it was mainly combined with coenzyme,anion,vitamin,serine type peptidase,protein kinase A and organic cyclic compounds in the molecular function,and involved in cancer cells,neurotrophic signals,insulin signals,metabolic pathways,insulin resistance and other signaling pathways in biological processes.In addition,the main cell groups involved were myelin formation,extracellular region,organelle outer membrane,mitochondria,mitotic DNA damage checkpoint,protein mitochondrial localization and so on.The results of KEGG Pathway analysis showed that it covered the positive regulation of cell movement,the regulation of apoptosis process,the regulation of biological quality,the response to external stimuli,the inter-cellular signal transduction,and the biological processes of protein metabolism.Conclusion:Firstly,based on the combination of EBM,network pharmacology and statistics,the BCMC combined with donepezil in the treatment of AD and its potential targets and mechanism of action could be revealed.Secondly,the BCMC named SYR might regulate the potential targets of MAPK14 and PTGS2 to inhibit the inflammatory response of cells,rule the participation of AR in the antioxidant stress response,adjust ESR1 to reduce the formation of A beta,and activate m TOR and BDNF to participate in neural development.Meanwhile,by participating in the insulin signaling pathway and the neurotrophic signaling pathway,the effect of donepezil might be enhanced via controlling various hormones,inflammatory responses and acetylcholine receptors,thereby intervening in the AD process and improving the cognitive and memory functions of AD patients.