Abstract
Necroptosis, which is mediated by RIP1/RIP3/MLKL (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein) signaling, is a critical process in the development of acute ischemic stroke. However, it is unclear precisely how necroptosis promotes the pathogenesis of acute ischemic stroke. In this experimental study in mice, we investigated how necroptosis loss-of-function mice, RIP1 kinase-dead mice, RIP3-deficiency mice, and MLKL-deficiency mice could be protected against cerebral injury after acute ischemic stroke. Insoluble RIP1, RIP3, and MLKL were all detected in the infarct area of the study mice, indicating activation of necroptosis. Two types of RIP1 kinase-dead mutant mice (Rip1K45A/K45A or Rip1Δ/Δ) were used to show that catalytically-inactive RIP1 can decrease the infarct volume and improve neurological function after MCAO/R (middle cerebral artery occlusion/reperfusion). Both Rip3−/− mice and Mlkl−/− mice were protected against acute ischemic stroke. In addition, necroptosis loss-of-function mice showed less inflammatory responses in the infarct area. Therefore, necroptosis and its accompanying inflammatory response can lead to acute injury following ischemia stroke. Our study provides new insight into the pathogenetic mechanisms of acute ischemic stroke, and suggests potential therapeutic targets for neuroprotection.
Highlights
Acute ischemic stroke is a common disease throughout the world with high mortality rates and high disability rates[1]
Necroptosis is activated in the infarct area after middle cerebral artery occlusion/reperfusion (MCAO/R) To investigate the pathogenesis of acute ischemic stroke, we firstly established the MCAO/R model to simulate cerebral ischemia-reperfusion injury
We examined the necroptosis-related gene (RIP1, RIP3, and MLKL) expression in the infarct area after MCAO/R
Summary
Acute ischemic stroke is a common disease throughout the world with high mortality rates and high disability rates[1]. In the pathogenesis of acute ischemic stroke, multiple cell death mechanisms occur, including necrosis, apoptosis, and autophagy[2,3]. Necrosis was considered a type of non-programed cell death differing from apoptosis, which is regulated by caspase cascades. Recent studies have demonstrated that necrotic cell death can be a regulated process, which is known as necroptosis[4,5,6,7]. Necroptosis is mediated by necrosomecontaining receptor-interacting protein kinase 1 (RIP1), Previous studies have verified that markers of necroptosis are increased in the ipsilateral striatum of the rat brain in the middle cerebral artery occlusion/reperfusion (MCAO/R) model[11,12,13]. Pharmacological data have demonstrated that necrostatin-1 (Nec-1), a necroptosis
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