methyl-thiohydantoin-tryptophan and Brain-Ischemia

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.

Topics: Animals; Brain Ischemia; Cell Death; Cell Line, Tumor; Humans; Imidazoles; Indoles; Mice; Molecular Structure; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins