Frontiers in Pharmacology (Mar 2022)

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

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

DOI
https://doi.org/10.3389/fphar.2022.832707
Journal volume & issue
Vol. 13

Abstract

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Objectives: 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.Methods: 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 in vitro. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals.Results: 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.Conclusion: 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.

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