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MCC950 Inhibits NLRP3 Inflammasome and Alleviates Axonal Injures in Early Stages of Diffuse Axonal Injury in Rats

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Abstract

Increasing evidence has revealed that neuroinflammation plays a pivotal role in axonal injures. Nucleotide oligomerization domain (NOD)-like receptor protein (NLRP3) inflammasome is reported to be widely involved with the pathology of central nervous system disorders. But the role of NLRP3 in diffuse axonal injury (DAI) are rarely reported. The purpose of this study was to investigate the expression of NLRP3 after diffuse axonal injury and the role of NLRP3 in axonal injures. The lateral head rotation device was used to establish DAI model of rats. Immunohistochemical staining for β-amyloid precursor protein and Bielschowsky silver staining were used to assess axonal injures and axonal loss. Terminal Deoxynucleotidyl Transferase-Mediated Digoxigenin-dUTP-Biotin Nick-End Labelling Assay was used to detect cell apoptosis. Brain water content was used to assess cerebral edema and the modified Neurologic Severity Score was used to assess the neurological deficits. Components of NLRP3 inflammasome, such as NLRP3, apoptosis-associated speck-like (ASC) adapter protein and caspase-1, and pro-inflammatory cytokines, for example IL-18 and IL-1β, were over-expressed in early stages of DAI. MCC950, a selective small-molecule inhibitor of NLRP3 inflammasome, inhibited the over-expression of NLRP3 inflammasome and pro-inflammatory cytokines after DAI. MCC950 alleviated axonal injures and cell apoptosis. MCC950 also decreased brain water content and alleviated neurologic deficits 1 day and 3 days after DAI but not 7 days after DAI. These results suggest that MCC950 treatment in the early stages of DAI has a time limiting effect in preventing from axonal injuries and neurological deficits, and that NLRP3 inflammasome plays an important role in axonal injures and may be a potential candidate for axonal injures following DAI.

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Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (No. 81471179) in funding this research. We also acknowledge Translational Medicine of the First Affiliated Hospital of Xi’an Jiaotong University for support of laboratory instruments.

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, Yanta Road 277, Xi’an, 710061, Shaanxi, China

    Junjie Zhao, Xiaoye Guo, Bo Wang, Zhongbo Yang & Jinning Song

  2. Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, Shaanxi, China

    Tingqin Huang & Ming Zhang

  3. Department of Science and Technology, Xi’an Medical University, Xi’an, 710021, Shaanxi, China

    Dan Guo

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Contributions

JZ and JS designed this research. JZ and JS wrote the article. JZ and BW performed the experiment. XG, DG and ZY did behavior tests and analyzed the experiments. TH and MZ did statistical analysis.

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Correspondence to Jinning Song.

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Zhao, J., Guo, X., Wang, B. et al. MCC950 Inhibits NLRP3 Inflammasome and Alleviates Axonal Injures in Early Stages of Diffuse Axonal Injury in Rats. Neurochem Res 45, 2020–2031 (2020). https://doi.org/10.1007/s11064-020-03063-6

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