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Prostanoids, not reactive oxygen species, mediate COX‐2–dependent neurotoxicity
Author(s) -
Manabe Yasuhiro,
Anrather Josef,
Kawano Takayuki,
Niwa Kiyoshi,
Zhou Ping,
Ross M. Elizabeth,
Iadecola Costantino
Publication year - 2004
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20078
Subject(s) - neurotoxicity , reactive oxygen species , neuroprotection , nmda receptor , glutamate receptor , pharmacology , superoxide dismutase , chemistry , cyclooxygenase , radical , prostaglandin , receptor , biochemistry , medicine , oxidative stress , enzyme , toxicity , organic chemistry
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. Ann Neurol 2004