Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice.
Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.
Iadecola
C
C
Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. iadec001@tc.umn.edu
Niwa
K
K
Nogawa
S
S
Zhao
X
X
Nagayama
M
M
Araki
E
E
Morham
S
S
Ross
M E
ME
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D003433:Crosses, Genetic; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D007839:Functional Laterality; D018698:Glutamic Acid / Q000633:toxicity; D006579:Heterozygote; D006720:Homozygote; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020768:Middle Cerebral Artery; D016202:N-Methylaspartate / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D007527:Isoenzymes; D008565:Membrane Proteins; D009498:Neurotoxins; D018698:Glutamic Acid; D016202:N-Methylaspartate; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone