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Pre-stroke Metformin Treatment is Neuroprotective Involving AMPK Reduction

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Abstract

Long-term metformin treatment reduces the risk of stroke. However, the effective administration pattern and indications of metformin on acute cerebral ischemia are unclear. To investigate the neuroprotective treatment duration and dosage of metformin on focal ischemia mice and the association of neuroprotection with 5′-adenosine monophosphate-activated protein kinase (AMPK) regulations, male C57BL/6 mice were subjected to permanent or transient middle cerebral artery occlusion (MCAO) and metformin of 3, 10 and 30 mg/kg was intraperitoneally injected 1, 3 or 7 days prior to MCAO, or at the onset, or 1, 3 or 6 h after reperfusion, respectively. Infarct volumes, neurological deficit score, cell apoptosis, both total and phosphorylated AMPK expressions were assessed. Results showed that prolonged pretreatment to 7 days of metformin (10 mg/kg) significantly ameliorated brain infarct, neurological scores and cell apoptosis in permanent MCAO mice. Shorter (3 days or 1 day) or without pretreatment of metformin was not effective, suggesting a pretreatment time window. In transient MCAO mice, metformin showed no neuroprotection even with pretreatment. The expressions of total and phosphorylated AMPK were sharply decreased with effective metformin pretreatments in ischemic brains. Our data provided the first evidence that in acute ischemic injury, a 7-days pretreatment duration of 10 mg/kg metformin is necessary for its neuroprotection, and metformin may not be beneficial in the cases of blood reperfusion.

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Acknowledgments

This work was funded by the National Natural Science Foundation of China (81373393, 81273506, 81273490 and 81402907), Zhejiang Provincial Natural Science Foundation (LR15H310001, LY15H090004), the Research Project of Department of Education of Zhejiang Province (Y201329908) and the Program for Zhejiang Leading Team of S&T Innovation Team (2011R50014).

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    Authors and Affiliations

    1. Institute of Pharmacology & Toxicology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

      Tian Deng, Yan-Rong Zheng, Wei-Wei Hou, Yang Yuan, Zhe Shen, Xiao-Li Wu, Ying Chen, Li-San Zhang, Wei-Wei Hu, Zhong Chen & Xiang-Nan Zhang

    2. Collaborative Innovation Center for Infectious Diseases Zhejiang University, Hangzhou, 310058, China

      Wei-Wei Hu, Zhong Chen & Xiang-Nan Zhang

    3. Key Laboratory of Cell-Based Drug and Application of Technology Research of Zhejiang Province (2014E10013), Hangzhou, China

      Ying Chen

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    1. Tian Deng
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    Correspondence to Xiang-Nan Zhang.

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    All experiments were approved by and conducted in accordance with the ethical guidelines of the Zhejiang University Animal Experimentation Committee and were in complete compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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    Tian Deng and Yan-Rong Zheng have contributed equally to this work.

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    Deng, T., Zheng, YR., Hou, WW. et al. Pre-stroke Metformin Treatment is Neuroprotective Involving AMPK Reduction. Neurochem Res 41, 2719–2727 (2016). https://doi.org/10.1007/s11064-016-1988-8

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    • DOI: https://doi.org/10.1007/s11064-016-1988-8

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