Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury.

Byung Hee Han, Daigen Xu, Junjeong Choi, Yongxin Han, Steven Xanthoudakis, Sophie Roy, John Tam, John Vaillancourt, John Colucci, Robert Siman, Andre Giroux, George S. Robertson, Robert Zamboni, Donald W. Nicholson, David M. Holtzman

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153 Citations (Scopus)

Abstract

Hypoxia-ischemia (H-I) in the developing brain results in brain injury with prominent features of both apoptosis and necrosis. A peptide-based pan-caspase inhibitor is neuroprotective against neonatal H-I brain injury, suggesting a central role of caspases in brain injury. Because previously studied peptide-based caspase inhibitors are not potent and are only partially selective, the exact contribution of specific caspases and other proteases to injury after H-I is not clear. In this study, we explored the neuroprotective effects of a small, reversible caspase-3 inhibitor M826. M826 selectively and potently inhibited both caspase-3 enzymatic activity and apoptosis in cultured cells in vitro. In a rat model of neonatal H-I, M826 blocked caspase-3 activation and cleavage of its substrates, which begins 6 h and peaks 24 h after H-I. Although M826 significantly reduced DNA fragmentation and brain tissue loss, it did not prevent calpain activation in the cortex. This activation, which is associated with excitotoxic/necrotic cell injury, occurred within 30 min to 2 h after H-I even in the presence of M826. Similar to calpain activation, we found evidence of caspase-2 processing within 30 min to 2 h after H-I that was not affected by M826. Caspase-2 processing appeared to be secondary to calpain-mediated cleavage and was not associated with caspase-2 activation. These data suggest that caspase-3 specifically contributes to delayed cell death and brain injury after neonatal H-I and that calpain activation is associated with and likely a marker for the early component of excitotoxic/necrotic brain injury previously demonstrated in this model.

Original languageEnglish
Pages (from-to)30128-30136
Number of pages9
JournalThe Journal of biological chemistry
Volume277
Issue number33
DOIs
Publication statusPublished - 2002 Aug 16

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Han, B. H., Xu, D., Choi, J., Han, Y., Xanthoudakis, S., Roy, S., Tam, J., Vaillancourt, J., Colucci, J., Siman, R., Giroux, A., Robertson, G. S., Zamboni, R., Nicholson, D. W., & Holtzman, D. M. (2002). Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury. The Journal of biological chemistry, 277(33), 30128-30136. https://doi.org/10.1074/jbc.M202931200