Reduced susceptibility to ischemic brain injury and N -methyl- d -aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

Reduced susceptibility to ischemic brain injury and N-methyl-d-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

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

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

Abstract

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.

Footnotes

↵ † 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.
Abbreviations:

NMDA,

N-methyl-d-aspartate;

COX,

cyclooxygenase;

MCA,

middle cerebral artery;

RT-PCR,

reverse transcription–PCR;

PBD,

porphobilinogen deaminase;

CBF,

cerebral blood flow;

PGE2,

prostaglandin E2