title: Inhibition of cyclooxygenase 2 by nimesulide improves cognitive outcome more than motor outcome following diffuse traumatic brain injury in rats.
abstract: Prostanoid synthesis is regulated by the enzyme cyclo-oxygenase (COX) that is present in at least two isoforms: COX-1, the constitutive form, and COX-2, the inducible form. Expression of COX-2 has recently been shown to be an important determinant of the cytotoxicity connected with inflammation following ischemic injury to the brain. The present study examines the temporal and spatial profiles of COX-2 expression following diffuse traumatic brain injury (TBI) in rats, and the effects of the COX-2 inhibitor nimesulide on cognitive and motor outcomes. Adult, male Sprague-Dawley rats were injured using the 2-meter impact acceleration model of diffuse TBI. At preselected time points after injury, animals were killed and the expression of COX-2 was measured in the hippocampus and parietal cortex by immunohistochemistry and Western blotting techniques. Effects of nimesulide (6 mg/kg daily over ten days) on cognitive and motor outcome was assessed in a separate group of animals using the Barnes circular maze and rotarod test, respectively. A highly significant up-regulation of COX-2 expression was found in the hippocampus as early as 3 h post-trauma and persisting for at least 12 days after TBI. In contrast, a slight but significant upregulation of COX-2 expression occurred in the cortex only at 3 days after trauma. Administration of the COX-2 inhibitor nimesulide resulted in a significant and substantial improvement in cognitive function compared to vehicle-treated controls, while motor deficits after injury was only improved at 24 h after injury. We conclude that COX-2 is involved in the development of functional deficits following diffuse TBI, particularly cognitive deficits, and that these can be improved by administration of COX-2 inhibitors.
authors.affiliation: Department of Neuroscience, Georgetown University, Washington DC, USA.
authors.forename: Ibolja
authors.initials: I
authors.lastname: Cernak
authors.forename: Christine
authors.initials: C
authors.lastname: O'Connor
authors.forename: Robert
authors.initials: R
authors.lastname: Vink
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology; D003071:Cognition / Q000187:drug effects*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D020833:Diffuse Axonal Injury / Q000188:drug therapy / Q000201:enzymology; D006624:Hippocampus / Q000201:enzymology*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010296:Parietal Lobe / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide