Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia

Eduardo Candelario-Jalil, Armando González-Falcón, Michel García-Cabrera, Dalia Álvarez, Said Al-Dalain, Gregorio Martínez, Olga Sonia León, Joe E. Springer

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

Abstract

We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.

Original languageEnglish
Pages (from-to)545-555
Number of pages11
JournalJournal of Neurochemistry
Volume86
Issue number3
DOIs
StatePublished - Aug 2003

Keywords

  • Cerebral ischemia
  • Cyclooxygenase
  • Hippocampal cell loss
  • Oxidative stress
  • Rofecoxib
  • Valeryl salicylate

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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