Two caspase-2 transcripts are expressed in rat hippocampus after global cerebral ischemia

Kunlin Jin, Tetsuya Nagayama, Xiaoou Mao, Kenji Kawaguchi, Robert W. Hickey, David A. Greenberg, Roger P. Simon, Steven H. Graham

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20 Scopus citations

Abstract

Caspase family genes play a critical role in the initiation and execution of programmed cell death. Programmed cell death is an important contributor to neuronal loss following cerebral ischemia. We have performed a series of experiments to investigate the role of a specific caspase, caspase-2, in the development of delayed neuronal death following transient global ischemia in the rat. A rat ischemic brain cDNA library was screened, and two splice-variants of caspase-2 mRNA were identified, caspase-2S and caspase-2L, which were highly homologous with the sequences of human and mouse caspase-2S and caspase-2L genes, respectively. RT-PCR demonstrated an increase in expression of both caspase-2S and caspase-2L mRNA at 8, 24 and 72 h of reperfusion after global ischemia. The ratio of the two PCR fragments did not change significantly throughout the time course of reperfusion. Western blot with monoclonal antibody specific to the proapoptotic caspase-2L splice variant revealed an increase in procaspase-2 (51 kDa) protein from 4 to 72 h following ischemia compared with sham-operated controls. Furthermore, an approximately 30-kDa cleavage product appeared at 8 h and increased with increasing duration of reperfusion. Thus, caspase-2L is both translated and activated following transient global ischemia. Finally, intraventricular administration of the caspase-2-like inhibitor (VDVAD-FMK) 30 min before induction of ischemia decreased the number of CA1 neurons staining positively for DNA damage (Klenow-labeling assay) and increased the number of healthy-appearing CA1 neurons (cresyl violet) compared with vehicle-treated controls. Taken together, the data suggest that caspase-2 induction and activation are important mediators of delayed neuronal death following transient global ischemia.

Original languageEnglish
Pages (from-to)25-35
Number of pages11
JournalJournal of Neurochemistry
Volume81
Issue number1
DOIs
StatePublished - 2002

Keywords

  • Caspase-2
  • Cell death
  • Gene expression
  • Inhibitor
  • Ischemia
  • Rat brain

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    Jin, K., Nagayama, T., Mao, X., Kawaguchi, K., Hickey, R. W., Greenberg, D. A., Simon, R. P., & Graham, S. H. (2002). Two caspase-2 transcripts are expressed in rat hippocampus after global cerebral ischemia. Journal of Neurochemistry, 81(1), 25-35. https://doi.org/10.1046/j.1471-4159.2002.00781.x