Haining Wang1, Hongping Chen1, Jing Jin1, Qingqing Liu1, Di Zhong2, Guozhong Li3. 1. Department of Neurology, The First Affiliated Hospital of Harbin Medical University, China. 2. Department of Neurology, The First Affiliated Hospital of Harbin Medical University, China. Electronic address: dityan@163.com. 3. Department of Neurology, The First Affiliated Hospital of Harbin Medical University, China. Electronic address: lgzhyd1962@163.com.
Abstract
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.
Authors: Radwa N Muhammad; Lamiaa A Ahmed; Rania M Abdul Salam; Kawkab A Ahmed; Amina S Attia Journal: Neurotherapeutics Date: 2021-10-18 Impact factor: 6.088