Role of cyclooxygenase 2 in acute spinal cord injury.
Cyclooxygenase, or prostaglandin G/H synthase, is the rate-limiting step in the production of prostaglandins. A new isoform, cyclooxygenase-2 (COX-2), has been cloned that is induced during inflammation in leukocytes and by synaptic activity in neurons. The objectives of this study are to determine the nature of COX-2 expression in normal and traumatized rat spinal cord, and to determine the effects of selective COX-2 inhibition on functional recovery following spinal cord injury. Using a weight-drop model of spinal cord injury, COX-2 mRNA expression was studied with in situ hybridization. COX-2 protein expression was examined by immunohistochemistry and Western analysis. Finally, using the highly selective COX-2 inhibitor, 1-[(4-methylsufonyl)phenyl]-3-tri-fluro-methyl-5-[(4-flur o)phenyl]prazole (SC58125), the effect of COX-2 inhibition on functional outcome following a spinal cord injury was determined. COX-2 was expressed in the normal adult rat spinal cord. COX-2 mRNA and protein production were increased following injury with increases in COX-2 mRNA production detectable at 2 h following injury. Increased levels of COX-2 protein were detectable for at least 48 h following traumatic spinal cord injury. Selective inhibition of COX-2 activity with SC58125 resulted in improved mean Basso, Beattie, and Bresnahan scores in animals with 12.5- and 25-g/cm spinal cord injuries; however, the effect was significant only for the 12.5g/cm injury group (p=0.0001 vs. p=0.0643 in the 25-g/cm group). These data demonstrate that COX-2 mRNA and protein expression are induced by spinal cord injury, and that selective inhibition of COX-2 improves functional outcome following experimental spinal cord injury.
Resnick
D K
DK
Department of Neurological Surgery, University of Wisconsin Medical School, Madison 53792, USA.
Graham
S H
SH
Dixon
C E
CE
Marion
D W
DW
D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010544:Peroxidases / Q000235:genetics* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D013116:Spinal Cord / Q000201:enzymology*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D012333:RNA, Messenger; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D010544:Peroxidases; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases