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Nature Chemical Biology 1, 112–119 (1 July 2005) | doi:10.1038/nchembio711

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

Alexei Degterev , Zhihong Huang , Michael Boyce , Yaqiao Li , Prakash Jagtap , Noboru Mizushima , Gregory D Cuny , Timothy J Mitchison , Michael A Moskowitz & Junying Yuan

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.