N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death

Nat Neurosci. 2012 Feb 26;15(4):574-80. doi: 10.1038/nn.3054.


Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x(L) is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-x(L), we generated knock-in mice expressing a caspase-resistant form of Bcl-x(L). The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x(L) could be a potentially important therapeutic target in ischemic brain injury.

Publication types

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

MeSH terms

  • Animals
  • Biphenyl Compounds / pharmacology
  • Biphenyl Compounds / therapeutic use
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology*
  • Brain Ischemia / prevention & control
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cells, Cultured
  • Female
  • Gene Knock-In Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology*
  • Nitrophenols / pharmacology
  • Nitrophenols / therapeutic use
  • Organ Culture Techniques
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • bcl-X Protein / biosynthesis
  • bcl-X Protein / genetics
  • bcl-X Protein / physiology*


  • ABT-737
  • Bcl2l1 protein, rat
  • Biphenyl Compounds
  • Nitrophenols
  • Piperazines
  • Sulfonamides
  • bcl-X Protein