Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats.
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 E(2) (PGE(2)) 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 PGE(2) levels 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.
Candelario-Jalil
Eduardo
E
Neurochemistry Research Group, Department of Psychiatry, University of Freiburg Medical School, Freiburg, Germany. ecandelario-jalil@salud.unm.edu
González-Falcón
Armando
A
García-Cabrera
Michel
M
León
Olga Sonia
OS
Fiebich
Bernd L
BL
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D009460:Neurologic Examination / Q000379:methods; D009195:Peroxidase / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D011458:Prostaglandins E; D012459:Salicylates; D013449:Sulfonamides; C401835:valerylsalicylate; D009195:Peroxidase; C012655:nimesulide