Article abstract


Nature Chemical Biology 1, 112 - 119 (2005)
Published online: 29 May 2005 | doi:10.1038/nchembio711



There is a Corrigendum (September 2005) associated with this Article.

There is an Addendum (March 2013) associated with this Article.

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

Alexei Degterev1, Zhihong Huang2, Michael Boyce1, Yaqiao Li1, Prakash Jagtap3, Noboru Mizushima4, Gregory D Cuny3, Timothy J Mitchison5, Michael A Moskowitz2 & Junying Yuan1


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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  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
  2. Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
  3. Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne St., Cambridge, Massachusetts 02139, USA.
  4. Department of Bioregulation and Metabolism, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
  5. Department of Systems Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

Correspondence to: Junying Yuan1 e-mail: jyuan@hms.harvard.edu



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