Identification of novel therapeutic targets for jaranol alleviating cognitive impairment in db/db mice

Abstract The widely used Radix Astragali (RA) has significant therapeutic effects on cognitive impairment (CI) caused by type 2 diabetes (T2DM). However, the effective active ingredients and the precise mechanism underly RA alleviation of T2DM-induced CI still require further study. In this study, we aim to elucidate whether and how jaranol, a key effective active ingredient in RA, influences CI in db/db mice. We used various online databases and Cytoscape to screen jaranol as the most active ingredient of RA in the treatment of T2DM-induced CI. The fear conditioning experiment, new object recognition (NOR) test, and Morris water maze (MWM) test were conducted to assess the improvement effect of jaranol on CI in diabetic mice. The protein-protein interaction (PPI) network, Cytoscape, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify key genes. The levels of AKT and caspase-3 were determined by Western blotting. The number of surviving hippocampal neurons was verified through Nissl staining. AutoDock was utilized for predicting potential binding sites between jaranol and key genes.As a result, jaranol attenuated CI in db/db mice probably through activation of PI3K-AKT signaling pathway by inhibiting cell apoptosis in hippocampus. Furthermore, A329 near the active site of AKT1 had hydrogen bond with jaranol. In conclusion, we suggest that jaranol may have therapeutic applications in T2DM-induced CI by targeting the PI3K-AKT signaling pathway directly via key sites. Our study provides alternative drugs and potential therapeutic targets for the prevention and treatment of T2DM-induced CI.