Results from several studies indicate that
cyclooxygenase-2 (COX-2) is involved in ischemic
brain injury. The purpose of this study was to evaluate the
neuroprotective effects of the selective
COX-2 inhibitor nimesulide on
cerebral infarction and neurological deficits in a standardized model of transient focal
cerebral ischemia in rats. Three doses of
nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after
stroke and additional doses were given at 6, 12, 24, 36 and 48 h after
ischemia. In other set of experiments, the effect of
nimesulide was studied in a situation in which its first administration was delayed for 3-24 h after
ischemia. Total, cortical and subcortical
infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after
ischemia. The effect of
nimesulide on
prostaglandin E(2) (
PGE(2)) levels in the injured brain was also investigated.
Nimesulide dose-dependently reduced
infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by
nimesulide (reduction of
infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after
ischemia. Further, administration of
nimesulide in a
delayed treatment paradigm completely abolished
PGE(2) accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for
cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage.