Integrated lipidomics and network pharmacology analysis of the protective effects and mechanism of Yuanzhi San on rats with cognitive impairment.

Cognitive impairment (CI) can seriously affect people's mental and physical health. Yuanzhi San (YZS) is a classic prescription for treating CI, but the mechanisms need further exploration. The aim of this study is to explore the effect of YZS on promoting the learning and memory ability of CI rats induced by d-galactose combined with aluminum chloride. Behavioral experiments had been used to comprehensively evaluate the established CI model. Brain histological morphology and the expressions of calcium ion signaling pathway related factors in serum were used to evaluate the effect of YZS against CI. Lipids in rat serum were analyzed by ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS) and chemical pattern recognition methods. Network pharmacology was used to find potential chemical compounds, targets, and related signaling pathways against CI with treatment of YZS. The integrated lipidomics and network pharmacology analysis were conducted by Cytoscape software. The results showed that YZS could alleviate neurodegenerative impairment. It was verified that model rats had longer latency time, shorter exploration paths, lower new objects recognition indexes, and shorter exercise time and distances compared with the normal rats in behavioral experiments, indicating that the model rats were successfully established. Rats of YZS 6.67 had significant differences in retention time (p < 0.05), number of entrances (p < 0.01), new object recognition indexes (p < 0.05, p < 0.01), exercise time (p < 0.05), and content of Ca [2], CAM, APP, CREB (p < 0.01), CAMK2 (p < 0.05). Rats of YZS 6.67 had five cell layers in hippocampus histological morphology. Behavioral experiments results showed that YZS had an active effect on CI rats. From lipidomics analysis, 129 lipids were screened out by conditions of VIP > 1 and p < 0.05, and 17 lipid markers were identified from the databases, which were divided mainly into five types. Pathway analysis indicated that linoleic acid, α-linolenic acid, arachidonic acid, and glycerophospholipid metabolisms were potential target pathways closely involved in the mechanism YZS's effects against CI. Network pharmacology focused on 84 chemical compounds, 130 intersection targets, and 10 hub genes of YZS's effects against CI. Six hub genes and four lipid compounds had intrinsic contact with arachidonic acid metabolism, glycerophospholipid metabolism and linoleate metabolism. The study revealed that YZS could improve animal cognitive behaviors, the expression of factors associated with memory in serum and the histological morphology of hippocampus. Four lipid compounds, three metabolic pathways, and six hub genes of YZS could effectively modulated CI. These results collectively suggest that the main mechanism of YZS in improving CI involves lipid metabolism, which affects biological processes and targets of action in the body.