AUTHOR=Hu Yan , Zhou Yile , Yang Yajie , Tang Haihong , Si Yuan , Chen Zhouyi , Shi Yi , Fang Hao 

TITLE=Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.832707

DOI=10.3389/fphar.2022.832707

ISSN=1663-9812

ABSTRACT=<p><bold>Objectives:</bold> Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment.</p><p><bold>Methods:</bold> Cognitive functions were examined by novel object recognition and T-maze tests. Mice hippocampi were collected for electron microscopy and immunofluorescence examination. Neuron cell line HT22 and primary hippocampal neurons were challenged with high glucose <italic>in vitro</italic>. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals.</p><p><bold>Results:</bold> Diabetic mice exhibited memory loss and spatial disorientation. Electron microscopy revealed that diabetic mice had larger synaptic gaps, attenuated postsynaptic density and fewer dendritic spines in the hippocampus. More round-shape mitochondria were observed in hippocampal neurons in diabetic mice than those in control mice. In cultured neurons, high glucose induced a high phosphorylated level of dynamin-related protein 1 (DRP1) and increased oxidative stress, resulting in cell apoptosis. Inhibition of mitochondrial fission by Mdivi-1 and metformin significantly decreased oxidative stress and prevented cell apoptosis in cultured cells. Treatment of Mdivi-1 and metformin restored cognitive function in diabetic mice.</p><p><bold>Conclusion:</bold> Metformin restores cognitive function by inhibiting mitochondrial fission, reducing mitochondrial-derived oxidative stress, and mitigating neuron loss in hippocampi of diabetic mice. The protective effects of metformin shed light on the therapeutic strategy of cognitive impairment.</p>