Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota, U.S.A.

Correspondence: Costantino Iadecola, University of Minnesota Medical School, Department of Neurology, MMC 295, 516 Delaware Street SE, Minneapolis, MN 55455, U.S.A.

Received 25 June 2001; Revised 17 August 2001; Accepted 17 August 2001.

Abstract

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-methl- d -asparatate 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.