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NLRP3 Inflammasome Is Involved in Q-VD-OPH Induced Necroptosis Following Cerebral Ischemia-Reperfusion Injury

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Abstract

Necroptosis is a manner of caspase-independent cell death,which accounts for delayed ischemic cerebral injury, and can be used as a novel tool to expand the treatment time window in ischemic cerebral injury. Q-VD-OPH, a novel pan caspase inhibitor, has been identified as an inducer of necroptosis. In this study, we determined the optimal dose of Q-VD-OPH, which induces necroptosis in rats by the middle cerebral artery occlusion, followed by reperfusion. Furthermore, we report that the NLRP3 inflammasome is involved in necroptosis, with levels of NLRP3 inflammasome proteins as well as inflammatory cytokines, such as IL-1β, being elevated. We also demonstrated that NLRP3 was not only expressed in microglia and vascular endothelial cell, but also in neurons when necroptosis is induced with Q-VD-OPH. Inhibition of NLRP3 by glyburide strongly suppressed the expression of NLRP3 inflammasome proteins and IL-1β, and markedly reduced brain tissue damage. Our findings provide evidence that pretreatment with Q-VD-OPH suppresses apoptosis and induces necroptosis in the cerebral ischemia-reperfusion model. We also identified that the NLRP3 inflammasome plays an important role in neuronal necroptosis, and that NLRP3 inflammasome deficiency reduces brain tissue damage after cerebral ischemia-reperfusion injury in rats.

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Acknowledgements

This study was supported by Grants 81501138 from the National Natural Science Foundation of China and KC15SH077 from Xuzhou Science and Technology Project. We would like to thank Hongyan Dong, Ting Li and Fuxing Dong from Laboratory of Neurobiology Research Center of Xuzhou Medical University for advices and help.

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Authors and Affiliations

  1. Xuzhou Medical University, Xuzhou, 221004, China

    Xue Teng, Zhihan Liu, Sheng Ding, Ying Zhang & Xianping Tang

  2. Neurology Department of The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

    Deqin Geng

  3. Neurology Department of Xuzhou Central Hospital, Xuzhou, 221009, China

    Weiwei Chen

  4. Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, China

    Tao Feng

  5. Department of Clinical Pharmacy of Xuzhou Central Hospital, Xuzhou, 221009, China

    Yonggang Chen

  6. Jiangsu Key Laboratory of Brain Disease Bioinformation of Xuzhou Medical College, Xuzhou, 221009, China

    Hui Li

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  1. Xue Teng
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  3. Zhihan Liu
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Xue Teng and Weiwei Chen are co-first authors.

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Teng, X., Chen, W., Liu, Z. et al. NLRP3 Inflammasome Is Involved in Q-VD-OPH Induced Necroptosis Following Cerebral Ischemia-Reperfusion Injury. Neurochem Res 43, 1200–1209 (2018). https://doi.org/10.1007/s11064-018-2537-4

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