Inhibttion Of Ferroptosis In Hippocampal Neurons Improves Cognitive Dysfunction In Mice With Type 2 Diabetes

【Research background and purpose】Cognitive dysfunction is a growing complication of type 2 diabetes,and we called it"mild cognitive impairment"（MCI）until the early levels of cognitive dysfunction were low.If cognitive dysfunction cannot be reversed in the early stages of symptoms,prolonged pathogenesis may lead to dementia and Alzheimer’s disease（AD）.Ferroptosis,a new type of cell death,plays an important role in nervous system damage.In this study,we will explore the effect of inhibiting ferroptosis of hippocampal neurons on the improvement of cognitive dysfunction in mice with type 2 diabetes,which will provide new evidence for ferroptosis as a new target for the diagnosis and treatment of type 2 diabetes cognitive dysfunction.【Methods】1.The purchased C57/BL6 mice were given normal diet adaptive feeding for 1 week,and then randomly divided into 2 groups.10 mice in the normal diet group（NOR）and 21 mice in the model group（T2DM）were treated with high-fat diet for 4 weeks and a one-time intraperitoneal injection of STZ（100mg/kg）.Mice with type 2 diabetes were screened by measuring their body weight,fasting blood glucose,serum cholesterol,triglyceride and serum insulin levels.2.The model mice were randomly divided into two groups:the model group and the lip-1 group（T2DM+Liproxstatin-1）.Three weeks later,the effect of liproxstatin-1 on spatial learning and memory ability of type 2 diabetic mice was observed by novel object recognition experiment and Y maze behavior test.The effect of liproxstatin-1 on the number of neurons in the hippocampal CA1 region of type 2 diabetic mice was observed by HE staining after mice were sacrificed.The effects of liproxstatin-1 on the mitochondrial morphology of neurons in the hippocampal CA1 region of type 2 diabetic mice were observed by transmission electron microscopy.ELISA was used to observe the effects of liproxstatin-1 on the expression levels of GPX4,Fe²⁺,MDA,NADPH and ROS in the hippocampal tissues of type 2 diabetic mice.【Results】1.By detecting the levels of fasting blood glucose,blood lipid and serum insulin in mice,the results showed that the mice had fasting blood glucose of>11.1mmol/L and hyperlipidemia,which proved that the mouse model of type 2 diabetes was successfully established.2.Liproxstatin-1 could increase the correct alternate rate of Y maze and the recognition index of novel object recognition experiment in type 2diabetic mice.Liproxstatin-1 has a protective effect on hippocampal CA1neurons in type 2 diabetic mice.Liproxstatin-1 inhibited the expression of Fe²⁺,MDA and ROS in the hippocampus of type 2 diabetic mice.Liproxstatin-1 inhibited the expression of GPX4 and NADPH in the hippocampus of type 2 diabetic mice.【Conclusion】Inhibition of ferroptosis in hippocampal neurons improves cognitive dysfunction in mice with type 2 diabetes mellitus.