Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice.
Cyclooxygenase-1 (COX-1), a rate-limiting enzyme in the synthesis of prostanoids, is involved in selected vasodilatatory responses of the cerebral circulation. Cyclooxygenase-1-null mice were used to determine whether COX-1 influences cerebral ischemic damage. The middle cerebral artery was occluded in COX-1 -/- and +/+ mice (n = 9/group), and lesion volume was determined in thionin-stained sections 24 or 96 hours later. Middle cerebral artery occlusion produced larger infarcts in COX-1 -/- mice, both at 24 (35 +/- 17%; P < 0.05) and 96 hours (41 +/- 16%; P < 0.05) after ischemia. The enlargement was not due to increased susceptibility to glutamate excitotoxicity, because microinjection of N-methyl-D-aspartate or kainate in the parietal cortex produced comparable lesions in COX-1 +/+ and -/- mice ( P > 0.05; n = 8/group). To examine the contribution of hemodynamic factors to the enlargement of the infarct, cerebral blood flow was monitored by laser-Doppler flowmetry in the ischemic territory (n = 6/group). Although the reduction in cerebral blood flow was comparable in the ischemic core ( P > 0.05), at the periphery of the ischemic territory the reduction was greater in COX-1 -/- mice (-58 +/- 4%) than in COX-1 +/+ mice (-34 +/- 5%; P < 0.05). It is concluded that mice lacking COX-1 are more susceptible to focal cerebral ischemia, an effect that can be attributed to a more severe cerebral blood flow reduction in vulnerable regions at the periphery of the ischemic territory. Thus, the vascular effects of COX-1 may contribute to maintain cerebral blood flow in the postischemic brain and, as such, play a protective role in ischemic brain injury.
Iadecola
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Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Sugimoto
K
K
Niwa
K
K
Kazama
K
K
Ross
M E
ME
D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002560:Cerebrovascular Circulation; D051545:Cyclooxygenase 1; D004198:Disease Susceptibility; D018690:Excitatory Amino Acid Agonists; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics*; D007608:Kainic Acid; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate; D009498:Neurotoxins; D010296:Parietal Lobe / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011453:Prostaglandins / Q000378:metabolism; D020521:Stroke / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D018690:Excitatory Amino Acid Agonists; D007527:Isoenzymes; D008565:Membrane Proteins; D009498:Neurotoxins; D011453:Prostaglandins; D016202:N-Methylaspartate; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D007608:Kainic Acid