Browsing by Author "Cuny, Gregory D"
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Item Open Access Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury.(Nature chemical biology, 2005-07) Degterev, Alexei; Huang, Zhihong; Boyce, Michael; Li, Yaqiao; Jagtap, Prakash; Mizushima, Noboru; Cuny, Gregory D; Mitchison, Timothy J; Moskowitz, Michael A; Yuan, JunyingThe 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.