Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Yanta Road 277, Xi'an, 710061, Shaanxi, China.
Department of Neurosurgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
Neurochem Res. 2020 Sep;45(9):2020-2031. doi: 10.1007/s11064-020-03063-6. Epub 2020 May 30.
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.
越来越多的证据表明神经炎症在轴突损伤中起着关键作用。核苷酸寡聚化结构域（NOD）样受体蛋白（NLRP3）炎症小体被广泛报道与中枢神经系统疾病的病理学有关。但是，NLRP3 在弥漫性轴索损伤（DAI）中的作用很少有报道。本研究旨在探讨 NLRP3 在弥漫性轴索损伤后的表达及其在轴突损伤中的作用。使用侧头旋转装置建立大鼠 DAI 模型。β-淀粉样前体蛋白免疫组织化学染色和 Bielschowsky 银染色用于评估轴突损伤和轴突丢失。末端脱氧核苷酸转移酶介导的地高辛-dUTP-生物素缺口末端标记法用于检测细胞凋亡。脑水含量用于评估脑水肿，改良神经功能缺损评分用于评估神经功能缺损。在 DAI 的早期阶段，NLRP3 炎症小体的组成部分，如 NLRP3、凋亡相关斑点样（ASC）衔接蛋白和半胱天冬酶-1，以及促炎细胞因子，如 IL-18 和 IL-1β，过度表达。MCC950 是 NLRP3 炎症小体的一种选择性小分子抑制剂，可抑制 DAI 后 NLRP3 炎症小体和促炎细胞因子的过度表达。MCC950 减轻了轴突损伤和细胞凋亡。MCC950 还降低了 DAI 后 1 天和 3 天的脑水含量并减轻了神经功能缺损，但在 DAI 后 7 天没有减轻。这些结果表明，MCC950 在 DAI 早期治疗具有预防轴突损伤和神经功能缺损的时间限制作用，NLRP3 炎症小体在轴突损伤中起重要作用，可能是 DAI 后轴突损伤的潜在候选药物。
