title: Cyclooxygenase-2 activity contributes to neuronal expression of cyclin D1 after anoxia/ischemia in vitro and in vivo.
abstract: Cyclooxygenase-2 (COX-2) activity has been implicated in the pathogenesis of neuronal cell death in ischemia and other diseases, but the mechanism by which COX-2 exacerbates cell death is unknown. COX-2 activity is known to induce expression of cyclin D1 in neoplastic cells, and cyclin D1 expression can induce cell death in postmitotic neurons. In the present study, the role of COX-2 and cyclin D1 in neuronal cell death induced by anoxia and ischemia was examined. Treatment with the COX-2 specific inhibitor (NS 398 25 microM) and cyclin D1 inhibitor (flavopiridol 1 microM) increased neuronal survival and inhibited DNA fragmentation after anoxia. NS-398 suppressed anoxia-induced expression of cyclin D1. Flavopiridol inhibited the anoxia-induced increased expression of cyclin D1, but had no effect on COX-2 expression. Treatment with the selective COX-2 inhibitor, SC58125, had no affect on COX-2 expression but partially suppressed cyclin D1 expression in the cortex following middle cerebral artery occlusion in vivo. These results show that COX-2 activity is required for cyclin D1 expression after ischemia in vivo and anoxia in vitro. These data provide support for the hypothesis that cyclin D1 expression is an important mechanism by which COX-2 activity exacerbates ischemic neuronal death.
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Wu Chen
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Marie E
authors.initials: ME
authors.lastname: Rose
authors.forename: Steven H
authors.initials: SH
authors.lastname: Graham
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051546:Cyclooxygenase 2; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D018696:Neuroprotective Agents; D009578:Nitrobenzenes; D010880:Piperidines; D011720:Pyrazoles; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D019938:Cyclin D1; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; C077990:alvocidib; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases