Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China; Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, People's Republic of China.
Department of Drug Administration, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, People's Republic of China.
Tissue Cell. 2021 Aug;71:101514. doi: 10.1016/j.tice.2021.101514. Epub 2021 Feb 24.
NOD-like receptor protein 3 (NLRP3) inflammasome is tightly related to the pathogenesis of cerebral ischemia/reperfusion (I/R) injury, and oridonin (Ori) has shown the potential to alleviate ischemia/reperfusion injury with underlying mechanisms. Our study aims to figure out whether Ori protects against the cerebral ischemia/reperfusion injury by the NLRP3 inflammasome signaling. In this study, a temporary middle cerebral artery occlusion (MCAO) and reperfusion surgery was conducted on male C57BL/6 mice to mimic cerebral I/R injury in vivo. Cellular model of cerebral I/R in vitro was achieved by oxygen-glucose deprivation and reintroduction (OGD/R) in BV2 microglia cells. We found that Ori treatment significantly relieved the neurological deficits, neuronal injury and microglia activation in I/R mice according to morphological and histological analyses. Meanwhile, the inactivation of NLRP3 inflammasome was determined in Ori-treated mice with significantly down-regulated expressions of inflammasome-related genes. Western-blot analysis further demonstrated the negative effect of Ori on NF-κB signaling with diminished phosphorylation and degradation of IκBα as well as suppressed translocation of p65. Furthermore, we indicated that Ori suppressed the activation of NLRP3 inflammasome in OGD/R induced BV2 microglia cells by inhibiting NF-κB signaling. In summary, our findings make Ori a potential candidate for therapy of cerebral I/R injury in the future.
核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎症小体与脑缺血/再灌注（I/R）损伤的发病机制密切相关，冬凌草甲素（Ori）具有通过潜在机制减轻缺血/再灌注损伤的潜力。本研究旨在探讨 Ori 是否通过 NLRP3 炎症小体信号通路来保护脑缺血/再灌注损伤。在这项研究中，对雄性 C57BL/6 小鼠进行了短暂性大脑中动脉闭塞（MCAO）和再灌注手术，以在体内模拟脑 I/R 损伤。通过氧葡萄糖剥夺和再引入（OGD/R）在 BV2 小胶质细胞中建立体外脑 I/R 细胞模型。我们发现 Ori 处理可显著减轻 I/R 小鼠的神经功能缺损、神经元损伤和小胶质细胞激活，这可从形态学和组织学分析中得到证实。同时，在 Ori 处理的小鼠中发现 NLRP3 炎症小体失活，炎症小体相关基因的表达明显下调。Western blot 分析进一步表明，Ori 通过抑制 IκBα的磷酸化和降解以及抑制 p65 的易位，对 NF-κB 信号产生负向作用。此外，我们表明 Ori 通过抑制 NF-κB 信号抑制 OGD/R 诱导的 BV2 小胶质细胞中 NLRP3 炎症小体的激活。总之，我们的研究结果表明 Ori 可能是未来治疗脑 I/R 损伤的候选药物。
