α-asarone activates mitophagy to relieve diabetic encephalopathy via inhibiting apoptosis and oxidative stress

Diabetic encephalopathy (DE) is a common complication of diabetes that may result in cognitive impairment. Currently, there is limited effective therapy for DE. Herein, we explored the beneficial effect of α-Asarone on DE and its potential mechanisms. DE was induced in Type 2 diabetes mellitus mice and high-glucose (HG)-exposed PC-12 cells. Cognitive function was evaluated by MWM test. Pathological changes in the brain tissues were observed by HE staining. Cell viability was detected by CCK-8. Apoptosis was assessed by Hoechst 33,342 staining, Annexin V/PI staining and TUNEL. Mitochondrial membrane potential was analyzed by JC-1 probe. ROS production was measured by DCFH-DA staining. Target protein levels were analyzed by Western blotting. Network pharmacology was used to elucidate the beneficial mechanisms of α‐Asarone in DE. Our study showed that α‐Asarone enhanced cell viability and suppressed apoptosis in HG-stimulated PC-12 cells. Furthermore, α‐Asarone relieved HG-induced reduction in mitochondrial membrane potential and ROS overproduction. In addition, mitophagy was triggered by α‐Asarone, which was responsible for the inhibitory effect of α‐Asarone on apoptosis and oxidative stress. Consistently, the in vivo experiments showed that α‐Asarone treatment relieved cognitive dysfunction, apoptosis, and oxidative stress of DE mice via mitophagy induction. However, inhibition of mitophagy by Mdivi-1 counteracted the beneficial action of α‐Asarone. Mechanistically, network pharmacology analysis identified 10 key targets of α‐Asarone. Molecular docking substantiated a strong affinity of α‐Asarone with CASP3, EGFR, NFKB1, and ESR1 proteins. Taken together, α‐Asarone protected against mitochondrial dysfunction, oxidative stress and apoptosis via activating mitophagy, thereby alleviating DE. Our findings suggest α‐Asarone as a potential drug for DE. Graphical