Mechanism of Panax notoginseng saponins in improving cognitive impairment induced by chronic sleep deprivation based on the integrative analysis of serum metabolomics and network pharmacology

Abstract

Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, its protective mechanism on the central nervous system (CNS) is not clear. The present study initially evaluated the possible mechanism of PNS to improve cognitive dysfunction due to chronic sleep deprivation (CSD). In the present study, we used a modified multi-platform aquatic environment sleep deprivation method to induce a cognitively impaired rat model, and explored the mechanism of action of PNS by integrating serum metabolomics and network pharmacology, which was further verified by molecular docking and experiments. The results showed that PNS significantly shortened the escape latency, increased the target quadrant time and the number of traversing platforms, and attenuated the inflammatory damage in the hippocampal Cornu Ammonis 1 (CA1) region in CSD rats. The non-targeted metabolomics results indicated that 35 biomarkers significantly altered following PNS therapy intervention, with metabolic pathways enriched for the effects of One carbon pool by folate, Riboflavin metabolism, Glycerophospholipid metabolism, Sphingolipid metabolism, Glycerolipid metabolism, Arachidonic acid metabolism, and Tryptophan metabolism. In addition, network pharmacology identified 234 potential targets for PNS intervention in CSD with cognitive impairment. Metabolite-response-enzyme-gene network was constructed by MetaScape and matched with the network pharmacology results to identify a total of five shared targets (LPL, GPAM, HSD11B1, HSD11B2, and SULT2A1) and two metabolic pathways (Sphingolipid metabolism and Steroid hormone biosynthesis). The results of molecular docking revealed that the five active ingredients had good binding ability with the five core targets. qPCR analysis confirmed the ability of PNS to modulate the above five targets. The combination of metabolomics and network analysis provides a scientific basis for promoting the clinical application of PNS in cognitive impairment.