1. Academic Validation
  2. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

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

  • Nat Chem Biol. 2005 Jul;1(2):112-9. doi: 10.1038/nchembio711.
Alexei Degterev 1 Zhihong Huang Michael Boyce Yaqiao Li Prakash Jagtap Noboru Mizushima Gregory D Cuny Timothy J Mitchison Michael A Moskowitz Junying Yuan
Affiliations

Affiliation

  • 1 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
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.

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