Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation.
Cyclooxygenase-2 (COX-2) expression is induced in the neurons of the pathologic brain and elevated COX-2 expressions can lead to neuronal death. Here, we report that COX-2 induction in cortical neurons induced by LPS pretreatment for more than 12 h increased the neurotoxic effects of low doses of Fe2+ by more than 2.5-fold. Moreover, the neurotoxicity induced by 30 muM Fe2+ in LPS-pretreated cells exceeded that induced by 100 microM Fe2+ in LPS-untreated cells. LPS pretreatment also similarly aggravated the neurotoxic effects of low doses of H2O2, Zn2+, and sodium nitroprusside. This LPS-induced Fe2+ -toxicity enhancement was blocked by trolox, vitamin C, the SOD mimetic MnTBAP, and by the COX-2-specific inhibitor NS398, but not by inhibitors of xanthine oxidase, NADPH oxidase, NOS, and monoamine oxidase. Cortical neurons with enhanced COX-2 expression showed superoxide generation, GSH depletion, and lipid peroxidation in response to low doses of Fe2+, and all of these changes were repressed by MnTBAP or NS398. Consistent with this pharmacological data, cortical neurons prepared from COX-2 knockout mice showed marked reductions in LPS-induced Fe2+ -toxicity enhancement and superoxide generation. These results suggest that COX-2 functions as a cellular factor which induces superoxide-mediated cell death in primary cortical neurons.
Im
Joo-Young
JY
Division of Nano Science and Department of Life Sciences, Ewha Womans University, 11-1, Daehyun-Dong, Seodaemoon-Gu, Seoul, Republic of Korea.
Kim
Doyeun
D
Paik
Sang-Gi
SG
Han
Pyung-Lim
PL
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000201:enzymology*; D002712:Chlorides; D003513:Cycloheximide / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005290:Ferric Compounds / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009599:Nitroprusside / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D002712:Chlorides; D005290:Ferric Compounds; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D013481:Superoxides; D009599:Nitroprusside; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; C024555:ferric chloride