<br>二甲双胍通过调节 AMPK/ULK1/PINK1/Parkin 通路介导的线粒体自噬和细胞凋亡减轻因高血糖而加重的脑缺血/再灌注损伤,Chemico-Biological Interactions

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二甲双胍通过调节 AMPK/ULK1/PINK1/Parkin 通路介导的线粒体自噬和细胞凋亡减轻因高血糖而加重的脑缺血/再灌注损伤
Chemico-Biological Interactions ( IF 4.7 ) Pub Date : 2023-09-21 , DOI: 10.1016/j.cbi.2023.110723
Yaqi Guo ₁ , Haifeng Jiang ₂ , Meng Wang ₃ , Yanmei Ma ₃ , Jianzhong Zhang ₃ , Li Jing ₃

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中风仍然是全球死亡和残疾的主要主要原因，糖尿病是其重要的独立风险因素。据报道，二甲双胍作为治疗 2 型糖尿病的有效降糖药，可以降低糖尿病相关中风的风险。然而，其潜在机制仍不清楚。本研究旨在探讨线粒体自噬及其调节途径在二甲双胍对高血糖加重的脑缺血/再灌注（I/R）损伤的神经保护机制中的作用。实验采用高血糖脑 I/R 动物模型和高糖培养氧-葡萄糖剥夺/再灌注（OGD/R）细胞模型。观察脑损伤、细胞活性、线粒体形态和功能、线粒体自噬、线粒体通路凋亡和 AMPK 通路等指标。在糖尿病大鼠中，二甲双胍治疗减少了脑梗死体积和神经元凋亡，并改善了 I/R 损伤后的神经系统症状。此外，二甲双胍诱导 AMPK/ULK1/PINK1/Parkin 线粒体自噬通路的激活具有神经保护作用。在体外，高葡萄糖培养和 OGD/R 治疗损害了线粒体形态和功能、线粒体膜电位并诱导细胞凋亡。然而，二甲双胍激活了 AMPK/ULK1/PINK1/Parkin 线粒体自噬通路，使线粒体损伤正常化。自噬抑制剂 3-甲基腺嘌呤（3MA）和 AMPK 抑制剂化合物 C 逆转了这种保护作用。总之，我们目前的研究验证了二甲双胍通过激活 AMPK/ULK1/PINK1/Parkin 线粒体自噬通路缓解高血糖加重脑 I/R 损伤的潜在机制。

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

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.

更新日期：2023-09-21

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