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.