Ischemic post-conditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats

Authors

  • Rong Xie,

    1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
    3. Department of Neurosurgery, Shanghai Jingan District Central Hospital, Shanghai, China
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  • Peng Wang,

    1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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  • Xunming Ji,

    1. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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  • Heng Zhao

    Corresponding author
    1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA
    2. Stanford Stroke Center, Stanford University School of Medicine, Stanford, California, USA
    • Address correspondence and reprint requests to Heng Zhao, Department of Neurosurgery, Stanford University School of Medicine, MSLS Bldg., Room P306, 1201 Welch Rd., Stanford, CA 94305-5327, USA. E-mail: hzhao@stanford.edu

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Abstract

While pre-conditioning is induced before stroke onset, ischemic post-conditioning (IPostC) is performed after reperfusion, which typically refers to a series of mechanical interruption of blood reperfusion after stroke. IPostC is known to reduce infarction in wild-type animals. We investigated if IPostC protects against brain injury induced by focal ischemia in Tcell–deficient nude rats and to examine its effects on Akt and the mammalian target of rapamycin (mTOR) pathway. Although IPostC reduced infarct size at 2 days post-stroke in wild-type rats, it did not attenuate infarction in nude rats. Despite the unaltered infarct size in nude rats, IPostC increased levels of phosphorylated Akt (p-Akt) and Akt isoforms (Akt1, Akt2, Akt3), and p-mTOR, p-S6K and p-4EBP1 in the mTOR pathway, as well as growth associated Protein 43 (GAP43), both in the peri-infarct area and core, 24 h after stroke. IPostC improved neurological function in nude rats 1–30 days after stroke and reduced the extent of brain damage 30 days after stroke. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC. We determined that IPostC did not inhibit acute infarction in nude rats but did provide long-term protection by enhancing Akt and mTOR activity during the acute post-stroke phase.

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Post-conditioning did not attenuate infarction in nude rats measured 2 days post-stroke, but improved neurological function in nude rats and reduced brain damage 30 days after stroke. It resulted in increased-activities of Akt and mTOR, S6K and p-4EBP1. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC.

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