Dihydromyricetin ameliorates neurotoxicity induced by high glucose through restraining ferroptosis by inhibiting JNK-inflammation pathway in HT22 cells

Abstract

Diabetes mellitus is recognized as an important cause of cognitive dysfunction. Ferroptosis plays a key role in diabetic cognitive dysfunction (DCD). Dihydromyricetin (DHM) has promising neuronal protective effects, but it is unclear the mechanism. Here, the effects of DHM on HG-induced neurotoxicity in HT22 cells and its molecular mechanisms were investigated. Our results demonstrated that the viability of HG (125 mmol/L)-induced HT22 cells was significantly decreased. Furthermore, ferroptosis-related indicators, c-Jun N-terminal kinase (JNK)-inflammatory pathway, TNF-α, IL-1β, and mitochondrial morphology were measured. The results show that mitochondria of HT22 cells also showed wrinkled alterations in response to HG treatment. Meanwhile, the levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4) were decreased, accompanied by an up-regulation of malondialdehyde (MDA), Fe²⁺, acyl-CoA synthetase long-chain family member 4 (ACSL4), and reactive oxygen species (ROS), indicating ferroptosis occurred in HG-induced HT22 cells. Furthermore, the levels of p-JNK, TNF-α, and IL-6 were up-regulated in HG-induced HT22 cells. DHM or JNK inhibitor SP600125 reversed these changes in HG-induced HT22 cells indicating that HG-induced neurotoxicity in HT22 cells may be associated with ferroptosis induced by the JNK-inflammatory factor pathway. Meanwhile, JNK agonist Anisomycin could attenuate these effects of DHM. Taken together, our data suggest that DHM can ameliorate HG-induced neurotoxicity in HT22 cells by inhibiting ferroptosis via the JNK-inflammatory signaling pathway. Hence, DHM may represent a novel and promising therapeutic intervention for DCD.