Journal
JOURNAL OF NEUROCHEMISTRY
Volume 86, Issue 3, Pages 545-555Publisher
WILEY
DOI: 10.1046/j.1471-4159.2003.01812.x
Keywords
cyclooxygenase; cerebral ischemia; hippocampal cell loss; oxidative stress; rofecoxib; valeryl salicylate
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Funding
- NINDS NIH HHS [NS40015, R01 NS040015] Funding Source: Medline
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We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E-2 (PGE(2)) 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 PGE(2) levels after 2 and 24-48 h of reperfusion. The late increase in PGE(2) 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.
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