Metformin alleviates cerebral ischemia/reperfusion injury aggravated by hyperglycemia via regulating AMPK/ULK1/PINK1/Parkin pathway-mediated mitophagy and apoptosis

Yaqi Guo; Haifeng Jiang; Meng Wang; Yanmei Ma; Jianzhong Zhang; Li Jing

doi:10.1016/j.cbi.2023.110723

Metformin alleviates cerebral ischemia/reperfusion injury aggravated by hyperglycemia via regulating AMPK/ULK1/PINK1/Parkin pathway-mediated mitophagy and apoptosis

Chem Biol Interact. 2023 Oct 1:384:110723. doi: 10.1016/j.cbi.2023.110723. Epub 2023 Sep 21.

Authors

Yaqi Guo¹, Haifeng Jiang², Meng Wang³, Yanmei Ma³, Jianzhong Zhang³, Li Jing⁴

Affiliations

¹ Department of Pathology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China; Clinical Laboratory Center, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
² Department of Pathology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
³ Department of Pathology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
⁴ Department of Pathology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China. Electronic address: 19970015@nxmu.edu.cn.

PMID: 37741536
DOI: 10.1016/j.cbi.2023.110723

Abstract

Stroke remains the main leading cause of death and disabilities worldwide, with diabetes mellitus being a significant independent risk factor for it. Metformin, as an efficient hypoglycemic drug in treating type 2 diabetes, has been reported to alleviate the risk of diabetes-related stroke. However, its underlying mechanisms remain unclear. This study aimed to investigate the role of mitophagy and its regulatory pathway in the neuroprotective mechanism of metformin against cerebral ischemia/reperfusion (I/R) injury aggravated by hyperglycemia. A hyperglycemic cerebral I/R animal model and a high glucose cultured oxygen-glucose deprivation/reperfusion (OGD/R) cell model were used in the experiment. The indexes of brain injury, cell activity, mitochondrial morphology and function, mitophagy, mitochondrial pathway apoptosis and the AMPK pathway were observed. In diabetic rats, metformin treatment decreased cerebral infarction volume and neuronal apoptosis, and improved neurological symptoms following I/R injury. Additionally, metformin induced activation of the AMPK/ULK1/PINK1/Parkin mitophagy pathway to have neuroprotective effects. In vitro, high glucose culture and OGD/R treatment impaired mitochondrial morphology and function, mitochondrial membrane potential, and induced apoptosis. However, metformin activated AMPK/ULK1/PINK1/Parkin mitophagy pathway, normalized mitochondrial injury. This protection was reversed by autophagy inhibitor 3-methyladenine (3MA) and AMPK inhibitor compound C. In conclusion, our present study validates the potential mechanism of metformin in alleviating hyperglycemia aggravated cerebral I/R injury by the activation of AMPK/ULK1/PINK1/Parkin mitophagy pathway.

Keywords: AMPK; Cerebral I/R injury; Hyperglycemia; Metformin; Mitophagy.