Activation of Akt/FoxO signaling pathway contributes to induction of neuroprotection against transient global cerebral ischemia by hypoxic pre-conditioning in adult rats

Authors

  • Lixuan Zhan,

    1. Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical College; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Tao Wang,

    1. Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical College; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Wen Li,

    1. Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical College; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Zao C. Xu,

    1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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  • Weiwen Sun,

    1. Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical College; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • En Xu

    1. Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical College; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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Address correspondence and reprint requests to Dr En Xu, Institute of Neurosciences, the Second Affiliated Hospital of Guangzhou Medical College, 250 Changgang Dong RD, Guangzhou 510260, China. E-mail: enxu@163.net

Abstract

J. Neurochem. (2010) 114, 897–908.

Abstract

It is well established that pre-conditioning protects neuronal injury against ischemia. However, the molecular mechanisms underlying ischemic tolerance are not completely understood. The purpose of the present study was to investigate the role of Akt/forkhead transcription factor, class O (FoxO) pathway in hypoxic pre-conditioning (HPC) using a newly developed HPC to transient global cerebral ischemia (tGCI) model in adult rats. HPC for 30–120 min significantly reduced cell death in the CA1 subregion after 10 min of tGCI. HPC was effective only when applied 1–4 days before ischemia. The maximum protection was observed with 30 min of hypoxia and 1 day interval between hypoxia and ischemia. The phosphorylated Akt and FoxOs measured by western blot and immunohistochemistry were significantly increased after hypoxia-ischemia except for a transient decrease in the HPC group. Lateral ventricular infusion of LY294002 before HPC blocked the increase in phosphorylated Akt and FoxOs and increased neuronal damage in HPC animals. These results suggest that pre-exposure to hypoxia induces protection against tGCI in adult rats. Activation of Akt results in the inactivation of FoxOs which may mediate ischemic tolerance after HPC.

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