Artemisinin Improves Cognitive Impairment In Type 2 Diabetic Mice By Inhibiting Hippocampal Ferroptosis Via Activating Nrf2

?Objective?This study will explore that artemisinin improves cognitive impairment in type 2 diabetes mice,and reveal the mechanism whether it inhibit hippocampal ferroptosis via activating Nrf2.It will expand new thinking to understand the pathogenesis of cognitive impairment in type 2 diabetes and provide a new way for the prevention and treatment.?Methods?1.High-fat diet combined with streptozotocin intraperitoneal injection was used to construct mouse model of type 2 diabetes.Cognitive function was evaluated by novel object recognition and Y maze behavior test,and the mouse with cognitive impairment of type 2 diabetes were selected.2.The experimental animals were randomly divided into three groups: normal group,model group and artemisinin treatment group(40 mg/kg/d).The cognitive function of mice in each group was evaluated by novel object recognition,Y maze and Morris water maze behavioral tests.The histological morphology of CA1 in hippocampus was observed by HE staining,and the morphology of hippocampal mitochondria was observed by electron microscopy.The chemical contents of GSH,ROS and MDA in hippocampal tissues were detected by Elisa,and the protein contents of Nrf2,HO-1 and GPX4 in hippocampal tissues were determined by western blots.3.Mice was treated with Nrf2 inhibitor ML385 or ferroptosis inducer Erastin in combination with artemisinin.They were divided into five groups randomly: normal group,model group,artemisinin treatment group,artemisinin treatment + ML385 group,and artemisinin treatment + Erastin group.The same methods were used to evaluate the cognitive function and Nrf2 and ferroptosis in mice.?Results?1.The fasting blood glucose of mice with type 2 diabetes exceed 11.1 mmol/L,the serum total cholesterol,triglyceride and insulin levels were increased,as well as insulin resistance index.The cognitive function decreased in mice with type 2 diabetes cognitive impairment,successfully built the model.2.Compared with the model group,the cognitive function of mice was significantly improved after artemisinin treatment.The tissue morphology and mitochondrial damage in the hippocampal CA1 region were improved,ROS and MDA contents were relatively reduced,Nrf2 and HO-1 protein expressions were significantly increased,GSH and GPX4 protein expressions were relatively increased.3.When the mice treated with Nrf2 inhibitor ML385 or ferroptosis inducer Erastin in combination with artemisinin,the improvement in cognitive function of model group mice was reversed.,and the tissue morphology and mitochondrial damage in the CA1 region of hippocampus were not improved.After ML385 was used,the expression of Nrf2 and HO-1 proteins in the hippocampus was significantly inhibited,and the content of ROS and MDA increased,while the GSH content and GPX4 protein expression decreased.After Erastin was used,the content of ROS and MDA increased significantly,GSH and GPX4 decreased significantly,and the protein expression of Nrf2 and HO-1 decreased slightly.?Conclusion?Artemisinin improves cognitive impairment in type 2 diabetic mice by inhibiting hippocampal ferroptosis via activating Nrf2.