Integrated Lipidomics and Network Pharmacology Reveal Mechanism of Memory Impairment Improvement by Yuanzhi San.

Memory impairment (MI) is caused by a variety of causes, endangering human health. Yuanzhi San (YZS) is a common prescription used for the treatment of MI, but its mechanism of action needs further exploration. The purpose of this study was to investigate this mechanism through lipidomics and network pharmacology. Sprague Dawley (SD) rats were divided randomly into the normal, model, and YZS groups. The rats were gavaged with aluminum chloride (200 mg/kg) and intraperitoneally injected with D-galactose (400 mg/kg) every day for 60 days, except for the normal group. From the 30 day, YZS (13.34 g/kg) was gavaged once a day to the rats in the YZS group. Post-YZS treatment, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC/MS) analysis was implemented to conduct a lipidomics study in the hippocampus of rats with memory impairment induced by aluminum chloride and D-galactose. Eight differential metabolites were identified between the normal group and the model group, whereas between the model group and the YZS group, 20 differential metabolites were established. Metabolic pathway analysis was performed on the aforementioned lipid metabolites, all of which were involved in sphingolipid and glycerophospholipid metabolism. Furthermore, serum pharmacochemistry analysis of YZS was carried out at the early stage of our research, which discovered 62 YZS prototype components. The results of the network pharmacology analysis showed that they were related to 1030 genes, and 451 disease genes were related to MI. There were 73 intersections between the YZS and MI targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these targets were closely related to the sphingolipid metabolic, calcium signaling, and other pathways. The integrated approach of lipidomics and network pharmacology was then focused on four major targets, including PHK2, GBA, SPTLC1, and AChE, as well as their essential metabolites (glucosylceramide, N-acylsphingosine, phosphatidylserine, phosphatidylcholine, and phosphatidylcholine) and pathways (sphingolipid, glycerophospholipid, and arachidonic acid metabolism). The significant affinity of the primary target for YZS was confirmed by molecular docking. The obtained results revealed that the combination of lipidomics and network pharmacology could be used to determine the effect of YZS on the MI biological network and metabolic state, and evaluate the drug efficacy of YZS and its related mechanisms of action.