基于网络药理学、分子模拟及实验验证探讨益脑胶囊治疗阿尔茨海默病的作用机制OA

Objective To investigate the potential mechanism of Yinao Capsules in the treatment of Alzheimer disease(AD)through network pharmacology,molecular simulation,molecular dynamics simulations,and experimental validation.Methods Network pharmacology methods were comprehensively applied to screen active components and potential targets of Yinao Capsules for AD treatment,and a drug-component-target network was constructed.GO and KEGG pathway enrichment analyses were performed on the intersection targets.Molecular docking and molecular dynamics simulations were used to verify binding interactions of core components and targets.Taking C57BL/6 mice as the normal group,APP/PS1 transgenic mice were randomly divided into model group,donepezil hydrochloride group(0.65 mg/kg)and Yinao Capsules low-and high-dosage groups(351 and 1 404 mg/kg),and were intervened for 60 days.Cognitive ability was evaluated using novel object recognition and Morris water maze tests.Hippocampal CA1 neuronal morphology was observed via HE staining.Serum contents of IL-6 and TNF-α were detected by ELISA.Protein expressions of CASP3 and BCL2 in brain tissue were measured by Western blot.Results Network pharmacology identified 66 active components,including deoxyharringtonine and ginsenoside Rg5_qt,and 218 potential targets,with AKT1,IL6,and CASP3 as core targets.The enrichment analysis results of GO and KEGG pathways showed that Yinao Capsules intervened in AD through protein phosphorylation,G protein coupled receptor signal pathway coupled with cyclic nucleotide second messenger,positive regulation of ERK1 and ERK2 cascade reaction and Alzheimer disease,neuroactive ligand receptor interaction,neurodegenerative disease pathway-a variety of diseases,cell apoptosis and other pathways.Molecular docking and dynamics simulations confirmed that β-sitosterol and GSK3B form a stable complex.Animal experiments showed that Yinao Capsules significantly improved cognitive function in mice(P<0.05,P<0.01),reduced serum IL-6 and TNF-α contents(P<0.05),up-regulated BCL2 protein expression and inhibited CASP3 protein activation(P<0.05),and reduced neuronal loss in the hippocampal CA1 region.Conclusion Yinao Capsules can exert synergistic effects through multiple components,regulating key signaling nodes such as AKT1/GSK3β and IL-6/TNF-α,inhibiting neuroinflammation and apoptosis,thereby improving cognitive function and hippocampal pathological damage in AD model mice.Its mechanism involves multiple signaling pathways including AD-related pathways.