Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy |
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Authors: | Teng Jiang Jin-Tai Yu Xi-Chen Zhu Hui-Fu Wang Meng-Shan Tan Lei Cao Qiao-Quan Zhang Li Gao Jian-Quan Shi Ying-Dong Zhang Lan Tan |
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Institution: | 1.Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China;2.Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China;3.Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, China;4.Central Laboratory, Nanjing Brain Hospital, Nanjing Medical University, China;5.Department of Neurology, Nanjing First Hospital, Nanjing Medical University, China |
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Abstract: | BACKGROUND AND PURPOSERecent clinical trials report that metformin, an activator of AMP-activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk of stroke by actions that are independent of its glucose-lowering effects. However, the underlying molecular mechanisms are not known. Here, we tested the possibility that acute metformin preconditioning confers neuroprotection by pre-activation of AMPK-dependent autophagy in a rat model of permanent middle cerebral artery occlusion (pMCAO).EXPERIMENTAL APPROACHMale Sprague-Dawley rats were pretreated with either vehicle, an AMPK inhibitor, Compound C, or an autophagy inhibitor, 3-methyladenine, and were injected with a single dose of metformin (10 mg kg−1, i.p.). Then, AMPK activity and autophagy biomarkers in the brain were assessed. At 24 h after metformin treatment, rats were subjected to pMCAO; infarct volume, neurological deficits and cell apoptosis were evaluated 24 and 96 h later.KEY RESULTSA single dose of metformin significantly activated AMPK and induced autophagy in the brain. The enhanced autophagic activity was inhibited by Compound C pretreatment. Furthermore, acute metformin preconditioning significantly reduced infarct volume, neurological deficits and cell apoptosis during a subsequent focal cerebral ischaemia. The neuroprotection mediated by metformin preconditioning was fully abolished by Compound C and partially inhibited by 3-methyladenine.CONCLUSIONS AND IMPLICATIONSThese results provide the first evidence that acute metformin preconditioning induces autophagy by activation of brain AMPK, which confers neuroprotection against subsequent cerebral ischaemia. This suggests that metformin, a well-known hypoglycaemic drug, may have a practical clinical use for stroke prevention. |
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Keywords: | metformin autophagy stroke preconditioning AMPK neuroprotection |
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