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Ischemic Preconditioning Provides Neuroprotection by Induction of AMP-Activated Protein Kinase-Dependent Autophagy in a Rat Model of Ischemic Stroke

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Abstract

Accumulating evidence suggests that ischemic preconditioning (IPC) increases cerebral tolerance to the subsequent ischemic exposure. However, the underlying mechanisms are still not fully understood. In the present study, we tested the hypothesis that AMP-activated protein kinase (AMPK)-dependent autophagy contributed to the neuroprotection of IPC in rats with permanent cerebral ischemia. Male Sprague–Dawley rats were pretreated with vehicle, compound C (an AMPK inhibitor), or 3-methyladenine (3-MA, an autophagy inhibitor) and then were subjected to IPC induced by a 10-min middle cerebral artery occlusion. Afterward, the brain AMPK activity and autophagy biomarkers were measured. At 24 h after IPC, permanent cerebral ischemia was induced in these rats, and infarct volume, neurological deficits as well as cell apoptosis were evaluated 24 h later. We demonstrated that IPC activated AMPK and induced autophagy in the brain, which was accompanied by a reduction of infract volume, neurological deficits, and cell apoptosis after cerebral ischemia. Meanwhile, the IPC-induced autophagy was inhibited by compound C while the neuroprotection of IPC was abolished by compound C or 3-MA. These findings suggest that AMPK-mediated autophagy contributes to the neuroprotection of IPC, highlighting AMPK as a therapeutic target for stroke prevention and treatment.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China to L.T. (81171209, 81371406) and J.T.Y. (81000544), the Shandong Provincial Natural Science Foundation to L.T. (ZR2011HZ001) and J.T.Y. (ZR2010HQ004), the Medicine and Health Science Technology Development Project of Shandong Province to L.T. (2011WSA02018) and J.T.Y. (2011WSA02020), and the Innovation Project for Postgraduates of Jiangsu Province to T.J. (CXLX13_561).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China

    Teng Jiang, Jin-Tai Yu, Xi-Chen Zhu, Lei Cao, Hui-Fu Wang & Lan Tan

  2. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China

    Jin-Tai Yu & Lan Tan

  3. Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China

    Jin-Tai Yu, Meng-Shan Tan & Lan Tan

  4. Central Laboratory, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China

    Qiao-Quan Zhang

  5. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

    Jian-Quan Shi, Li Gao & Ying-Dong Zhang

  6. State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China

    Hao Qin

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  1. Teng Jiang
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Fig S1

The IPC-induced autophagy was significantly inhibited by pretreatment with 3-MA. Rats were pretreated with a single dose of 3-MA (200 nmol; i.c.v.) 5 min before they subjected to IPC. Twenty-four hours later, the protein levels of LC3-II was determined by western blotting. n=6 per group. Columns represent mean±SD. Abbreviations: Veh, Vehicle.1 (GIF 20 kb)

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Jiang, T., Yu, JT., Zhu, XC. et al. Ischemic Preconditioning Provides Neuroprotection by Induction of AMP-Activated Protein Kinase-Dependent Autophagy in a Rat Model of Ischemic Stroke. Mol Neurobiol 51, 220–229 (2015). https://doi.org/10.1007/s12035-014-8725-6

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