Opposing effects of cyclooxygenase-2 selective inhibitors on oxygen-glucose deprivation-induced neurotoxicity

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.