4.5 Article

Regulation of mitophagy by metformin improves the structure and function of retinal ganglion cells following excitotoxicity-induced retinal injury

期刊

EXPERIMENTAL EYE RESEARCH
卷 217, 期 -, 页码 -

出版社

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exer.2022.108979

关键词

Excitotoxicity; Metformin; Mitophagy; Neuroprotection; Mitochondria

资金

  1. National Natural Science Foundation of the People's Republic of China [82171055, 81770925, 81790641]
  2. Program of Shanghai Academic Research Leader [20XD1401100]
  3. Program for Outstanding Medical Academic Leader [2019LJ01]
  4. Shanghai Municipal Science and Technology Major Projects [2018SHZDZX05]
  5. Aging and Women's and Children's Health Special Project of Shanghai Municipal Health Commission [2020YJZX0102]

向作者/读者索取更多资源

This study found that metformin improves the structure and function of retinal neurons by regulating mitophagy. In vitro and in vivo experiments showed that metformin significantly increased cell viability and reduced apoptosis. In an animal model, metformin treatment significantly increased the number of surviving retinal ganglion cells and improved retinal function. Furthermore, metformin protected mitochondria by regulating the expression of mitophagy-related genes and proteins.
Excitotoxicity-induced retinal neuronal death is characterized by the progressive retinal ganglion cell (RGC) apoptosis. Strategies are needed to reduce neurodegeneration. Recent investigations have indicated the potential effects of metformin on multiple systems, especially in the networks. However, it also remains unclear whether mitophagy contributes to the neuroprotective effect of metformin on the retina. In this study, excitotoxicityinduced retinal injury models were constructed. In vitro, R28 cells were treated with calcium ionophore and metformin/phosphate-buffer saline (PBS). Cell viability, lactate dehydrogenase release, and the cellular apoptosis rate were assessed. In vivo, rats received intravitreal injection of N-methyl-D-aspartate and metformin/ PBS. Comprehensive examinations including retrograde fluorescent gold labelling, Nissl's staining, full-field electroretinography, photopic negative response, optic coherence tomography and retinal imaging, transmission electron microscopy, western blotting, and quantitative polymerase chain reaction were conducted during the observation period. The viability of R28 cells was significantly increased in the metformin-treated group compared with the negative control group, while, the release of lactate dehydrogenase and R28 cell apoptosis showed a significant decrease. In vivo, metformin treatment significantly increased the number of surviving RGCs, the b/NR wave amplitude and the thickness of the inner retina but had no obvious adverse effects on the fundus. In the metformin-treated group, the morphology and number of mitochondria were better preserved, as observed for RGCs; mitochondrial autophagosomes were located in RGCs, as indicated by transmission electron microscopy; and the expression of mitophagy-related genes and proteins presented was significant regulated. These data indicated that the regulation of mitophagy by metformin improved the structure and function of RGCs.

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