Prostanoids, not reactive oxygen species, mediate COX-2-dependent neurotoxicity.
The prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2) has emerged as a critical pathogenic factor in brain diseases associated with activation of N-methyl-D-aspartate (NMDA) receptors, including stroke and neurodegenerative diseases. However, the COX-2 reaction products responsible for these deleterious effects have not been identified. In particular, the relative contribution to the neurotoxicity of COX-2-derived prostanoids and reactive oxygen species has not been defined. We found that the brain damage produced by direct injection of NMDA into the somatosensory cortex is attenuated by the COX-2 inhibitor NS-398 or in COX-2-null mice, but that the associated production of free radicals is not. Furthermore, COX-2 inhibition reduces the lesions even if the deleterious effects of free radicals are eliminated by the scavenger superoxide dismutase. The protection exerted by NS-398 is counteracted by a stable analog of prostaglandin E2. The findings directly implicate COX-2-derived prostanoids, rather then radicals, in the COX-2-dependent component of the damage mediated by NMDA receptors and strengthen the rationale for using COX-2 inhibitors in the treatment of neurological diseases associated with glutamate neurotoxicity.
Manabe
Yasuhiro
Y
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA.
Anrather
Josef
J
Kawano
Takayuki
T
Niwa
Kiyoshi
K
Zhou
Ping
P
Ross
M Elizabeth
ME
Iadecola
Costantino
C
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000633:toxicity*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000633:toxicity*; D011453:Prostaglandins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000096:biosynthesis; D000072105:Superoxide Dismutase-1
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D016202:N-Methylaspartate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1