Post‐ischaemic treatment with the cyclooxygenase‐2 inhibitor nimesulide reduces blood–brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats

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Abstract
Several studies suggest that cyclooxygenase (COX)‐2 plays a pivotal role in the progression of ischaemic brain damage. In the present study, we investigated the effects of selective inhibition of COX‐2 with nimesulide (12 mg/kg) and selective inhibition of COX‐1 with valeryl salicylate (VAS, 12–120 mg/kg) on prostaglandin E2(PGE2) levels, myeloperoxidase (MPO) activity, Evans blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischaemia in the rat. Post‐ischaemic treatment with nimesulide markedly reduced the increase in PGE2levels in the ischaemic cerebral cortex 24 h after stroke and diminished infarct size by 48% with respect to vehicle‐treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood–brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischaemic episode. These studies provide the first experimental evidence that COX‐2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischaemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischaemia, confirming a wide therapeutic window of COX‐2 inhibitors in experimental stroke. On the contrary, selective inhibition of COX‐1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX‐2 activity, but not COX‐1 activity, contributes to the progression of focal ischaemic brain injury, and that the beneficial effects observed with non‐selective COX inhibitors are probably associated to COX‐2 rather than to COX‐1 inhibition.