title: Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia.
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.
authors.affiliation: Brain Injury Research Center, University of Kentucky Medical Center, Lexington, Kentucky 40536-0298, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Candelario-Jalil
authors.forename: Armando
authors.initials: A
authors.lastname: González-Falcón
authors.forename: Michel
authors.initials: M
authors.lastname: García-Cabrera
authors.forename: Dalia
authors.initials: D
authors.lastname: Alvarez
authors.forename: Said
authors.initials: S
authors.lastname: Al-Dalain
authors.forename: Gregorio
authors.initials: G
authors.lastname: Martínez
authors.forename: Olga Sonia
authors.initials: OS
authors.lastname: León
authors.forename: Joe E
authors.initials: JE
authors.lastname: Springer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D002452:Cell Count; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005849:Gerbillinae; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D013450:Sulfones
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D018696:Neuroprotective Agents; D012459:Salicylates; D013450:Sulfones; C401835:valerylsalicylate; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione; D015232:Dinoprostone