title: Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury.
abstract: 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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Boyce
authors.forename: Yaqiao
authors.initials: Y
authors.lastname: Li
authors.forename: Prakash
authors.initials: P
authors.lastname: Jagtap
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchison
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000187:drug effects; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C507699:necrostatin-1; D017346:Protein Serine-Threonine Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse