Necroptosis is one of the modalities of cell death accompanying ischemic brain stroke: from pathogenesis to therapeutic possibilities
Necroptosis is one of the modalities of cell death accompanying ischemic brain stroke: from pathogenesis to therapeutic possibilities
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DOI：
10.3325/cmj.2019.60.121
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发表时间：
2019-04-01
影响因子：
1.9
通讯作者：
Mitrecic, Dinko
中科院分区：
文献类型：
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作者：
Hribljan, Valentina;Lisjak, Damir;Mitrecic, Dinko
由于治疗选择非常有限，缺血性脑损伤是全世界死亡和终身残疾的主要原因之一，给公共卫生带来了巨大的负担。缺血性脑中风发生的主要事件之一是细胞死亡。坏死性凋亡是一种细胞死亡类型，被描述为调节性坏死，其特征是由磷酸化混合谱系激酶样蛋白 (MLKL) 介导的细胞膜破坏。它可以通过死亡受体（例如 FAS、TNFR1）的激活来触发，在缺乏活性 caspase-8 的情况下，RIPK1 会导致受体相互作用的丝氨酸/苏氨酸蛋白激酶 3 (RIPK3) 激活。在这里，我们回顾了报道坏死性凋亡显着导致缺血性脑中风发生的负面事件的文章，并且其抑制在体外和体内均具有保护作用。我们还回顾了描述通过减少坏死性凋亡获得的积极效果的文章，包括减少梗塞体积和改善动物模型的功能恢复。由于坏死性凋亡的特点是细胞内容物泄漏和随后的炎症，因此除了减少细胞死亡之外，抑制缺血性脑中风中的坏死性凋亡还可以减少一些炎症细胞因子。通过比较抑制坏死性凋亡的各种方法，我们从控制坏死性凋亡的角度分析所取得的效果，作为未来脑缺血治疗干预的一部分。
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.