Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

被引：2475

作者：

Degterev A. ^{[1
]}

Huang Z. ^{[2
]}

Boyce M. ^{[1
]}

Li Y. ^{[1
]}

Jagtap P. ^{[3
]}

Mizushima N. ^{[4
]}

Cuny G.D. ^{[3
]}

Mitchison T.J. ^{[5
]}

Moskowitz M.A. ^{[2
]}

Yuan J. ^{[1
]}

机构：

[1] Department of Cell Biology, Harvard Medical School, Boston, MA, 02115

[2] Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital Harvard Medical School, Charlestown, MA, 02129

[3] Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Brigham & Women’s Hospital and Harvard Medical School, Cambridge, MA, 02139

[4] Department of Bioregulation and Metabolism, The Tokyo Metropolitan Institute of Medical Science, Tokyo, 113-8613, 3-18-22 Honkomagome, Bunkyo-ku

[5] Department of Systems Biology, Harvard Medical School, Boston, MA, 02115

来源：

Nature Chemical Biology | 2005年 / 1卷 / 2期

关键词：

D O I：

10.1038/nchembio711

中图分类号：

学科分类号：

摘要：

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. © 2005, Nature Publishing Group. All rights reserved.

引用

页码：112 / 119

页数：7

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