Acute Administration of Metformin Protects Against Neuronal Apoptosis Induced by Cerebral Ischemia-Reperfusion Injury via Regulation of the AMPK/CREB/BDNF Pathway.
Acute Administration of Metformin Protects Against Neuronal Apoptosis Induced by Cerebral Ischemia-Reperfusion Injury via Regulation of the AMPK/CREB/BDNF Pathway.
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急性施用二甲双胍可通过调节 AMPK/CREB/BDNF 通路来防止脑缺血再灌注损伤引起的神经元凋亡。
DOI：
10.3389/fphar.2022.832611
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发表时间：
2022
影响因子：
5.6
通讯作者：
Wang, Yong
中科院分区：
文献类型：
--
作者：
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
关键词：
二甲双胍是一线抗糖尿病药，具有强大的降血糖作用。多项研究报道二甲双胍可以改善中风患者的预后，并且这种作用与其降血糖作用无关；但具体机制仍不清楚。本研究通过构建体内短暂性大脑中动脉闭塞模型和体外糖缺氧/复氧（OGD/R）模型，探讨二甲双胍治疗脑缺血再灌注（I/R）损伤的作用及具体机制。体内实验结果表明，小剂量二甲双胍（10 mg/kg）急性治疗可改善脑水肿，减少脑梗塞体积，改善神经功能缺损评分，并改善缺血半暗带的神经元凋亡。此外，二甲双胍上调缺血半暗带中脑源性神经营养因子（BDNF）的表达并增加AMP激活蛋白激酶（AMPK）和cAMP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化合物C逆转。体外实验结果表明，低浓度二甲双胍（20μM）可以减少OGD/R条件下人脐静脉内皮细胞（HUVEC）的凋亡，促进细胞增殖。此外，二甲双胍可以通过AMPK/CREB途径进一步促进OGD/R条件下HUVECs中BDNF的表达和释放。 Transwell小室实验表明，在OGD/R条件下，用二甲双胍处理的HUVEC可以减少SH-SY5Y细胞的凋亡，并且这种效应可以通过在HUVEC中转染BDNF siRNA来部分逆转。综上所述，我们的结果提示二甲双胍通过 AMPK/CREB 通路上调脑缺血半暗带 BDNF 水平，从而对脑 I/R 损伤发挥保护作用。
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 in vivo and a glucose and oxygen deprivation/reoxygenation (OGD/R) model in vitro. The results of the in vivo 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 in vitro 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 via 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 via the AMPK/CREB pathway, thereby playing a protective effect in cerebral I/R injury.
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影响因子：
14.5
作者：
Fitzgerald, Julia C.;Zimprich, Alexander;Krueger, Rejko
通讯作者：
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影响因子：
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DOI：
10.1124/jpet.112.197483
发表时间：
2013-02-01
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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