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PNAS | January 30, 2001 | vol. 98 | no. 3 | 1294-1299
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Pharmacology
 Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

(middle cerebral artery occlusion / prostanoids / cerebral blood flow / NS398 / stroke)

Costantino Iadecola*,dagger , Kiyoshi Niwa*, Shigeru Nogawa*, Xueren Zhao*, Masao Nagayama*, Eiichi Araki*, Scott MorhamDagger , and M. Elizabeth Ross*

* Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455; and Dagger  Myriad Genetics, Salt Lake City, UT 84108

Communicated by Philip Needleman, Monsanto Company, St. Louis, MO, November 21, 2000 (received for review July 27, 2000)

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.

dagger To whom reprint requests should be addressed at: Department of Neurology, University of Minnesota Medical School, Box 295, UMHC, 516 Delaware Street SE, Minneapolis, MN 55455. E-mail: iadec001{at}tc.umn.edu.


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