Abstract
Type 2 diabetes mellitus (T2DM) is frequently associated with diabetic cognitive impairment (DCI), and recent studies have shown a strong association between DCI and hippocampal ferroptosis. In this study, we administered dihydromyricetin (DHM) or JNK inhibitor SP600125, to T2DM rats and monitored changes in blood glucose levels, conducted behavioral tests, and detected changes in JNK, inflammatory factors and ferroptosis-related indicators. Our findings demonstrated that T2DM rats displayed signs of cognitive impairment (CI), with ferrozine assays indicating elevated iron content in the hippocampus. Concurrently, there was an increase in p-JNK activity and inflammatory factors IL-6 and TNF-α in the hippocampal region of these rats. Furthermore, we observed elevated levels of Fe2+, MDA, ROS, LPO, and ACSL4, along with a decrease in GPX4 and GSH, suggesting the occurrence of hippocampal ferroptosis. SP600125 application reversed these changes in the T2DM rats, although it exhibited no significant effects in the control group. Treatment with high and low doses of DHM led to a reduction in p-JNK expression, inflammatory factor-related proteins, and iron accumulation in the hippocampal region, effectively alleviating hippocampal ferroptosis in T2DM rats. No notable effects of DHM were observed in the control group. To conclude, our study suggests that DHM can potentially alleviate hippocampal ferroptosis of T2DM cognitive impairment rats, primarily by suppressing the JNK-inflammatory factor pathway in the hippocampus.
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