Astragalus Injection alleviates Diabetic Cognitive Impairment (DCI) through dual effects of anti-neuroinflammation and antioxidative stress based on network pharmacology analysis and experimental validation

Objective: To explore the effects of astragalus injection (AI) in patients with diabetic cognitive impairment (DCI). Methods: First, to screen for effective chemical components of astragalus, we searched Traditional Chinese Medicines Systems Pharmacology (TCMSP) and Analysis Platform databases. We then predicted the corresponding potential target genes using Swiss Target Prediction, searched and filtered three disease databases to identify DCI targets, and constructed a drug-component-target-disease interaction network and Protein-Protein Interaction (PPI) network. The core targets and pathways of AI against DCI were predicted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. In vivo experiments demonstrated the efficacy of AI in alleviating diabetes-associated cognitive impairment, whereas in vitro studies verified its anti-inflammatory and antioxidant stress mechanisms. Finally, western blot analysis identified key regulatory proteins involved in inflammation and oxidative stress, proposing a potential mechanism by which AI mitigates DCI through modulation of these proteins. Results: We screened 25 active components of astragalus and 251 drug targets and obtained 220 common targets after intersecting 8036 DCI targets. GO enrichment analysis showed that astragalus mainly treats DCI by regulating the response to external stimuli, lipopolysaccharide, hypoxia, and oxygen levels. KEGG pathway enrichment analysis revealed that it was mainly involved in cancer, calcium signaling, p53 signaling, vascular endothelial growth factor (VEGF) signaling pathway and Toll-like receptor (TLR) signaling pathways. Experimental results demonstrated that AI alleviates diabetes-associated cognitive impairment through dual mechanisms: activating the Keap1/Nrf2 signaling pathway to exert antioxidant effects, and inhibiting the TLR-4/NF-κB signaling pathway to mitigate neuroinflammation, thereby improving cognitive dysfunction and hyperglycemia. Conclusion: Network pharmacology identified potential AI interventions for DCI, and experiments were conducted to confirm some of the major targets in the predictive signaling pathway. Our study offers new insights into the mechanisms of AI treatment for DCI. Graphical abstract: http://links.lww.com/AHM/A205