Department of Neurology, The First Affiliated Hospital of Harbin Medical University, China.
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, China.
Life Sci. 2020 Jun 15;251:117638. doi: 10.1016/j.lfs.2020.117638. Epub 2020 Apr 3.
Brain edema is a common threat to life in ischaemic brain injury. The NLRP3 inflammasome promotes the inflammatory injury after ischaemic stroke. Previous studies have shown that aquaporin-4 (AQP4) modulates brain water transport and endothelin-1 (ET-1) induces cerebral edema. However, the contribution of the NLRP3 inflammasome to regulation of brain edema and blood-brain barrier (BBB) disruption in cerebral ischaemia-reperfusion is elusive. The aim of this study is to investigate the effect of inhibition of the NLRP3 inflammasome by MCC950 on regulation of cerebral edema, BBB disruption and the expression of AQP4 and ET-1 in cerebral ischaemia-reperfusion.
The male C57BL/6 mice were used to establish the experimental transient middle cerebral artery occlusion (tMCAO) model. The mice were intraperitoneally injected with MCC950. Changes in NLRP3, IL-1β, IL-18, the pyroptosis protein gasdermin D (GSDMD), brain water content, AQP4 and ET-1 in brain tissue were detected.
MCC950 inhibited NLRP3 and GSDMD after tMCAO. MCC950 improved cerebral edema and alleviated the damage of BBB after tMCAO. The levels of AQP4 and ET-1 were decreased by MCC950. In addition, MCC950 regulated the distribution of AQP4 after tMCAO in mice.
The NLRP3 inflammasome facilitated brain edema and BBB disruption after cerebral ischaemia-reperfusion in mice, and NLRP3 inflammasome inhibition with MCC950 regulated the expression and distribution of AQP4 in the infarct area. Hence, the NLRP3 inflammasome is considered to be an important target for the treatment of brain edema in cerebral ischaemia-reperfusion, and MCC950 has potential value for ischaemic stroke treatment.
脑水肿是缺血性脑损伤的常见生命威胁。NLRP3 炎性小体促进缺血性中风后的炎症损伤。先前的研究表明水通道蛋白-4（AQP4）调节脑水转运，内皮素-1（ET-1）诱导脑水肿。然而，NLRP3 炎性小体在脑缺血再灌注中调节脑水肿和血脑屏障（BBB）破坏的作用尚不清楚。本研究旨在探讨 MCC950 抑制 NLRP3 炎性小体对脑缺血再灌注中脑水肿、BBB 破坏以及 AQP4 和 ET-1 表达的调节作用。
雄性 C57BL/6 小鼠用于建立实验性短暂性大脑中动脉闭塞（tMCAO）模型。小鼠腹腔内注射 MCC950。检测 NLRP3、IL-1β、IL-18、细胞焦亡蛋白 gasdermin D（GSDMD）、脑组织含水量、AQP4 和 ET-1 的变化。
MCC950 抑制 tMCAO 后的 NLRP3 和 GSDMD。MCC950 改善 tMCAO 后的脑水肿并减轻 BBB 损伤。AQP4 和 ET-1 的水平降低。此外，MCC950 调节 tMCAO 后小鼠 AQP4 的分布。
NLRP3 炎性小体促进了小鼠脑缺血再灌注后的脑水肿和 BBB 破坏，MCC950 抑制 NLRP3 炎性小体调节了梗死区 AQP4 的表达和分布。因此，NLRP3 炎性小体被认为是治疗脑缺血再灌注后脑水肿的重要靶点，MCC950 对缺血性中风的治疗具有潜在价值。
