Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
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DOI：
10.1038/nchembio711
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发表时间：
2005-07-01
影响因子：
14.8
通讯作者：
Yuan, JY
中科院分区：
文献类型：
--
作者：
Degterev, A;Huang, ZH;Yuan, JY
在过去的十年中，细胞凋亡的机制已被广泛表征，但对调节细胞死亡的替代形式知之甚少。虽然Fas/TNFR受体家族的刺激触发了一个典型的“外在”凋亡途径，我们证明，在细胞内凋亡信号的情况下，它是能够激活一个共同的非凋亡性死亡途径，我们的术语坏死性凋亡。我们发现坏死性凋亡的特征是坏死细胞死亡形态和自噬激活。我们鉴定了一种特异性的有效的坏死性凋亡小分子抑制剂，坏死抑素-1，它阻断了坏死性凋亡的关键步骤。我们证明，坏死性凋亡有助于延迟小鼠缺血性脑损伤在体内通过不同的机制，细胞凋亡，并提供了一个新的治疗中风的神经保护窗口延长的目标。我们的研究确定了一个以前未描述的基本细胞死亡途径，与人类病理学具有潜在的广泛相关性。
The mechanism of apoptosis has been extensively characterized over the past decade, but little is known about alternative forms of regulated cell death. Although stimulation of the Fas/TNFR receptor family triggers a canonical 'extrinsic' apoptosis pathway, we demonstrated that in the absence of intracellular apoptotic signaling it is capable of activating a common nonapoptotic death pathway, which we term necroptosis. We showed that necroptosis is characterized by necrotic cell death morphology and activation of autophagy. We identified a specific and potent small- molecule inhibitor of necroptosis, necrostatin-1, which blocks a critical step in necroptosis. We demonstrated that necroptosis contributes to delayed mouse ischemic brain injury in vivo through a mechanism distinct from that of apoptosis and offers a new therapeutic target for stroke with an extended window for neuroprotection. Our study identifies a previously undescribed basic cell-death pathway with potentially broad relevance to human pathologies.