Caspase-3 mediated neuronal death after traumatic brain injury in rats

Robert S.B. Clark, Patrick M. Kochanek, Simon C. Watkins, Minzhi Chen, C. Edward Dixon, Neal A. Seidberg, John Melick, J. Eric Loeffert, Paula D. Nathaniel, Kun Lin Jin, Steven H. Graham

Research output: Contribution to journalArticle

305 Scopus citations

Abstract

During programmed cell death, activation of caspase-3 leads to proteolysis of DNA repair proteins, cytoskeletal proteins, and the inhibitor of caspase-activated deoxyribonuclease, culminating in morphologic changes and DNA damage defining apoptosis. The participation of caspase-3 activation in the evolution of neuronal death after traumatic brain injury in rats was examined. Cleavage of pro-caspase-3 in cytosolic cellular fractions and an increase in caspase-3-like enzyme activity were seen in injured brain versus control. Cleavage of the caspase-3 substrates DNA-dependent protein kinase and inhibitor of caspase-activated deoxyribonuclease and co-localization of cytosolic caspase-3 in neurons with evidence of DNA fragmentation were also identified. Intracerebral administration of the caspase-3 inhibitor N- benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (480 ng) after trauma reduced caspase-3-like activity and DNA fragmentation in injured brain versus vehicle at 24 h. Treatment with N-benzyloxycarbonyl-Asp-Glu-Val-Asp- fluoromethyl ketone for 72 h (480 ng/day) reduced contusion size and ipsilateral dorsal hippocampal tissue loss at 3 weeks but had no effect on functional outcome versus vehicle. These data demonstrate that caspase-3 activation contributes to brain tissue loss and downstream biochemical events that execute programmed cell death after traumatic brain injury. Caspase inhibition may prove efficacious in the treatment of certain types of brain injury where programmed cell death occurs.

Original languageEnglish
Pages (from-to)740-753
Number of pages14
JournalJournal of Neurochemistry
Volume74
Issue number2
DOIs
StatePublished - 29 Jan 2000

Keywords

  • Apoptosis
  • Cysteine protease
  • N-Benzyloxycarbonyl-Asp-Glu-Val-Asp- fluoromethyl ketone
  • Programmed cell death

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    Clark, R. S. B., Kochanek, P. M., Watkins, S. C., Chen, M., Dixon, C. E., Seidberg, N. A., Melick, J., Loeffert, J. E., Nathaniel, P. D., Jin, K. L., & Graham, S. H. (2000). Caspase-3 mediated neuronal death after traumatic brain injury in rats. Journal of Neurochemistry, 74(2), 740-753. https://doi.org/10.1046/j.1471-4159.2000.740740.x