Ischemic Preconditioning: Neuronal Survival in the Face of Caspase-3 Activation

Hidenobu Tanaka, Hidenori Yokota, Teresa Jover, Irene Cappuccio, Agata Calderone, Monica Simionescu, Michael V.L. Bennett, R. Suzanne Zukin

Research output: Contribution to journalArticlepeer-review

125 Scopus citations


Apoptosis is an evolutionarily conserved process critical to tissue development and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes inappropriate cell death. Global ischemia is a neuronal insult that induces delayed cell death with many features of apoptosis. Ischemic preconditioning affords robust protection of CA1 neurons against a subsequent severe ischemic challenge. The molecular mechanisms underlying ischemic tolerance are unclear. Here we show that ischemia induces pronounced caspase-3 activity in naive neurons that die and in preconditioned neurons that survive. Preconditioning intervenes downstream of proteolytic processing and activation of caspase-3 (a protease implicated in the execution of apoptosis) and upstream of the caspase-3 target caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA fragmentation) to arrest neuronal death. We further show that global ischemia promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), a factor that neutralizes the protective actions of IAPs and promotes neuronal death. Preconditioning blocks the mitochondrial release of Smac/DIABLO, but not the ischemia-induced upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death cascade and arrests neuronal death. These findings suggest that preconditioning preserves the integrity of the mitochondrial membrane, enabling neurons to survive in the face of caspase activation.

Original languageEnglish (US)
Pages (from-to)2750-2759
Number of pages10
JournalJournal of Neuroscience
Issue number11
StatePublished - Mar 17 2004


  • Apoptosis
  • Caspase death cascade
  • DNA fragmentation factor
  • Ischemic insults
  • Ischemic preconditioning
  • Neuronal death
  • Neuroprotection
  • Tolerance

ASJC Scopus subject areas

  • General Neuroscience


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