title: Opposing effects of cyclooxygenase-2 selective inhibitors on oxygen-glucose deprivation-induced neurotoxicity.
abstract: Cyclooxygenase-2 inhibitors protect against excitotoxicity in vitro yet provide conflicting results in in vivo models of ischemia. To bridge the gap in understanding the discrepancies among these studies, the effects of different cyclooxygenase-2 inhibitors were studied in an in vitro model of ischemia. Oxygen-glucose deprivation (OGD) induced cyclooxygenase-2 protein expression in neuronal cortical cultures. Cyclooxygenase-2 inhibitors exhibited opposing effects on neuronal death induced by OGD. The acidic sulfonamides, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) and N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide (nimesulide), aggravated neuronal death by enhancing OGD-induced increases in extracellular glutamate and intracellular Ca2+ levels. In contrast, 1-[(4-methylsulfonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl)pyrazole (SC-58125) dose-dependently protected cultures against OGD by suppressing increases in extracellular glutamate and intracellular Ca2+ levels. The NS-398-induced aggravation of neuronal death was lost if the inhibitor was added only following the OGD. The timing of inhibitor application also determined its effects on N-methyl-D-aspartate (NMDA)-induced excitoxicity. NS-398 was protective when added both during and post-NMDA exposure, but not if NS-398 was also applied for 60 min prior to the insult. In contrast, SC-58125 afforded protection against NMDA in the presence or absence of a pre-incubation period. This study demonstrates that certain cyclooxygenase-2 inhibitors have opposing effects on neuronal survival depending on the timing of application and the nature of the insult. These results may account for the discrepancies among previous studies which used different inhibitors and different models of neurotoxicity.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5. tania.gendron@nrc-cnrc.gc.ca
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Eric
authors.initials: E
authors.lastname: Brunette
authors.forename: Geoffrey A R
authors.initials: GA
authors.lastname: Mealing
authors.forename: Adele
authors.initials: A
authors.lastname: Nguyen
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Tauskela
authors.forename: Paul
authors.initials: P
authors.lastname: Morley
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002170:Canada; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005110:Extracellular Space / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D044882:Glucose Metabolism Disorders / Q000150:complications* / Q000378:metabolism / Q000517:prevention & control; D005971:Glutamates / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism; D009578:Nitrobenzenes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005971:Glutamates; D009578:Nitrobenzenes; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium; C012655:nimesulide