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Exogenous nitric oxide negatively regulates the S-nitrosylation p38 mitogen-activated protein kinase activation during cerebral ischaemia and reperfusion

Authors

  • S. H. Qi,

    1. Research Center for Biochemistry and Molecular Biology,
    2. Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China
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  • L. Y. Hao,

    1. Research Center for Biochemistry and Molecular Biology,
    2. Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China
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  • J. Yue,

    1. Research Center for Biochemistry and Molecular Biology,
    2. Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China
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  • Y. Y. Zong,

    1. Research Center for Biochemistry and Molecular Biology,
    2. Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China
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  • G. Y. Zhang

    Corresponding author
    1. Research Center for Biochemistry and Molecular Biology,
    2. Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China
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  • S. H. Qi and L. Y. Hao contributed equally to this work.

Guang-Yi Zhang, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, No. 84, W. Huai-Hai Road, Xuzhou 221002, China. Tel: +86 516 8574 8486; Fax: +86 516 8574 8486; E-mail: gyzhang@xzmc.edu.cn

Abstract

S. H. Qi, L. Y. Hao, J. Yue, Y. Y. Zong and G. Y. Zhang (2013) Neuropathology and Applied Neurobiology39, 284–297

Exogenous nitric oxide negatively regulates the S-nitrosylation p38 mitogen-activated protein kinase activation during cerebral ischaemia and reperfusion

Aims: A number of studies have suggested that nitric oxide (NO) plays an important role in the reactive phosphorylation of p38MAPKα (p38). However, whether S-nitrosylation of p38 is activated by NO and the details remain unclear. The aim of the present work was to assess the activation of p38, the S-nitrosylation site and the p38 signalling pathway in rat hippocampus and in HEK293 cell induced by exogenous NO. Methods: Primary hippocampal cultures, HEK293 cells and rat model of cerebral ischaemia/reperfusion (brain ischaemia was induced by four-vessel occlusion procedure) were used in this study. Biotin-switch method and immunoblotting were performed to study the S-nitrosylation and phosphorylation of p38, and neuronal loss was observed by histology. Results: Endogenous NO increased p38 phosphorylation and S-nitrosylation, and the activation of p38 was dependent on the S-nitrosylation of Cys-211, which was critical for the NO-mediated activation of p38. The exogenous NO donor sodium nitroprusside, S-nitrosoglutathione, 7-nitroindazole, the inhibitor of the neuronal nitric oxide synthase, inhibited the activation of p38 signal pathway induced by cerebral ischaemia/reperfusion and attenuated the damage in rat hippocampal neurones. Moreover, the N-methyl-D-aspartate receptor (NMDAR) is probably involved in the p38 activation process of S-nitrosylation and phosphorylation. Conclusion: Endogenous NO induces the S-nitrosylation and phosphorylation of p38 and mediates p38 signalling pathway by NMDAR, and as exogenous NO inhibits this process and is neuroprotective in rat cerebral ischaemia/reperfusion, it may make a contribution to stroke therapy.

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