Necroptosis is one of the modalities of cell death accompanying ischemic brain stroke: from pathogenesis to therapeutic possibilities.

Due to very limited therapeutic options, ischemic brain injury is one of the leading causes of death and lifelong disability worldwide, which imposes enormous public health burden. One of the main events occurring with ischemic brain stroke is cell death. Necroptosis is a type of cell death described as a regulated necrosis characterized by cell membrane disruption mediated by phosphorylated mixed lineage kinase like protein (MLKL). It can be triggered by activation of death receptors (eg, FAS, TNFR1), which lead to receptor-interacting serine/threonine-protein kinase 3 (RIPK3) activation by RIPK1 in the absence of active caspase-8. Here, we review articles that have reported that necroptosis significantly contributes to negative events occurring with the ischemic brain stroke, and that its inhibition is protective both in vitro and in vivo. We also review articles describing positive effects obtained by reducing necroptosis, including the reduction of infarct volume and improved functional recovery in animal models. Since necroptosis is characterized by cell content leakage and subsequent inflammation, in addition to reducing cell death, inhibition of necroptosis in ischemic brain stroke also reduces some inflammatory cytokines. By comparing various approaches in inhibition of necroptosis, we analyze the achieved effects from the perspective of controlling necroptosis as a part of future therapeutic interventions in brain ischemia.