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.