Liu Ke, Li Lulu, Liu Zhijun, Li Gang, Wu Yanqing, Jiang Xingjun, Wang Mengdie, Chang Yanmin, Jiang Tingting, Luo Jianheng, Zhu Jiahui, Li Hongge, Wang Yong
Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Department of Neurology, People's Hospital of Zhengzhou, People's Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
Front Pharmacol. 2022 Apr 1;13:832611. doi: 10.3389/fphar.2022.832611. eCollection 2022.
Metformin is a first-line anti-diabetic agent with a powerful hypoglycemic effect. Several studies have reported that metformin can improve the prognosis of stroke patients and that this effect is independent of its hypoglycemic effect; however, the specific mechanism remains unclear. In this research, we explored the effect and specific mechanism of metformin in cerebral ischemia-reperfusion (I/R) injury by constructing a transient middle cerebral artery occlusion model and a glucose and oxygen deprivation/reoxygenation (OGD/R) model . The results of the experiments showed that acute treatment with low-dose metformin (10 mg/kg) ameliorated cerebral edema, reduced the cerebral infarction volume, improved the neurological deficit score, and ameliorated neuronal apoptosis in the ischemic penumbra. Moreover, metformin up-regulated the brain-derived neurotrophic factor (BDNF) expression and increased phosphorylation levels of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB) in the ischemia penumbra. Nevertheless, the above-mentioned effects of metformin were reversed by Compound C. The results of the experiments showed that low metformin concentrations (20 μM) could reduce apoptosis of human umbilical vein endothelial cells (HUVECs) under OGD/R conditions and promote cell proliferation. Moreover, metformin could further promote BDNF expression and release in HUVECs under OGD/R conditions the AMPK/CREB pathway. The Transwell chamber assay showed that HUVECs treated with metformin could reduce apoptosis of SH-SY5Y cells under OGD/R conditions and this effect could be partially reversed by transfection of BDNF siRNA in HUVECs. In summary, our results suggest that metformin upregulates the level of BDNF in the cerebral ischemic penumbra the AMPK/CREB pathway, thereby playing a protective effect in cerebral I/R injury.
二甲双胍是一种具有强大降糖作用的一线抗糖尿病药物。多项研究报告称，二甲双胍可改善中风患者的预后，且这种作用独立于其降糖作用；然而，具体机制仍不清楚。在本研究中，我们通过构建短暂性大脑中动脉闭塞模型和葡萄糖及氧剥夺/复氧（OGD/R）模型，探讨了二甲双胍在脑缺血再灌注（I/R）损伤中的作用及具体机制。实验结果表明，低剂量二甲双胍（10 mg/kg）急性处理可减轻脑水肿，减少脑梗死体积，改善神经功能缺损评分，并减轻缺血半暗带区的神经元凋亡。此外，二甲双胍上调了缺血半暗带区脑源性神经营养因子（BDNF）的表达，并增加了AMP活化蛋白激酶（AMPK）和环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化水平。然而，二甲双胍的上述作用被Compound C逆转。实验结果表明，低浓度二甲双胍（20 μM）可减少OGD/R条件下人脐静脉内皮细胞（HUVECs）的凋亡并促进细胞增殖。此外，在OGD/R条件下，二甲双胍可通过AMPK/CREB途径进一步促进HUVECs中BDNF的表达和释放。Transwell小室实验表明，用二甲双胍处理的HUVECs可减少OGD/R条件下SH-SY5Y细胞的凋亡，而在HUVECs中转染BDNF siRNA可部分逆转这种作用。总之，我们的结果表明，二甲双胍通过AMPK/CREB途径上调脑缺血半暗带区BDNF的水平，从而在脑I/R损伤中发挥保护作用。
