title: Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Havana (CIEB-IFAL), Apartado Postal 6079, Havana City 10600, Cuba. candelariojalil@yahoo.com
authors.forename: Eduardo
authors.initials: E
authors.lastname: Candelario-Jalil
authors.forename: Armando
authors.initials: A
authors.lastname: González-Falcón
authors.forename: Michel
authors.initials: M
authors.lastname: García-Cabrera
authors.forename: Olga Sonia
authors.initials: OS
authors.lastname: León
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007118:Immunoassay / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000627:therapeutic use*; D013778:Tetrazolium Salts; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D013449:Sulfonamides; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D015232:Dinoprostone; C012655:nimesulide