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. Epub 2005 May 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Mice
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / antagonists & inhibitors
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism

Substances

  • Imidazoles
  • Indoles
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • necrostatin-1
  • Protein-Serine-Threonine Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse

Associated data

  • PubChem-Substance/841019
  • PubChem-Substance/841020
  • PubChem-Substance/841021
  • PubChem-Substance/841022
  • PubChem-Substance/841023
  • PubChem-Substance/841024
  • PubChem-Substance/841025
  • PubChem-Substance/841026
  • PubChem-Substance/841027
  • PubChem-Substance/841028