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.
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This work was supported in part by grants from the US National Institute of General Medicine (R01 GM64703) and National Institute on Aging (R37 AG012859) to J.Y., the National Institute of Neurological Disorders and Stroke (R01 NS37141-08) to M.M. and J.Y., and funding from the Harvard Center for Neurodegeneration and Repair to G.D.C. A.D. is a recipient of a National Institute on Aging Mentored Research Scientist Career Development Award and an American Health Assistance Foundation Pilot Award. We thank X. Teng for help in preparing compounds for animal testing; M. Lipinski and R. Olea-Sanchez for critical reading of the manuscript; C. Ayata for helpful suggestions with MCAO experiments; and G. Nunez, T. Jacks, J. Blenis and T. Yoshimori for providing RIP constructs, pSRP vector and mutant Jurkat cells, and anti-LC3 antibody, respectively.
The authors declare no competing financial interests.
Nec-1(1) specifically and efficiently inhibits apoptosis. (PDF 123 kb)
Nec-1 inhibits multiple necroptosis-associated morphological changes. (PDF 132 kb)
Additive effects of 7-Cl-Nec-1(3) and zVAD.fmk on inhibition of ischemia-induced neuronal death in vivo. (PDF 12 kb)
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Degterev, A., Huang, Z., Boyce, M. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1, 112–119 (2005). https://doi.org/10.1038/nchembio711
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