Neuroprotection by the selective cyclooxygenase-2 inhibitor SC-236 results in improvements in behavioral deficits induced by reversible spinal cord ischemia.
OBJECTIVE
Cyclooxygenase-2 (COX-2), an enzyme that is induced in the central nervous system after various insults, has been localized to neurons and in cells associated with the cerebral vasculature, where it may be involved in the inflammatory component of the ischemic cascade. COX-2 is part of the initial reaction that involves the arachidonic acid cascade, which produces molecules that support an inflammatory response. The present study evaluated the pharmacological effects of a specific long-acting COX-2 inhibitor, SC-236, in a reversible rabbit spinal cord ischemia model using clinical rating scores (behavioral analysis) as the primary end point.


METHODS
SC-236 was administered (10 to 100 mg/kg SC) 5 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (10 to 40 minutes) occlusion of the infrarenal aorta. Behavioral analysis, which allowed for the calculation of an ET(50) value representing the duration of ischemia (minutes) associated with a 50% probability of resultant permanent paraplegia, was conducted 18 and 48 hours later. A drug was determined to be neuroprotective if it prolonged the ET(50) significantly compared with the appropriate control group.


RESULTS
Since SC-236 is not readily soluble in aqueous solutions, it was dissolved in 100% dimethyl sulfoxide (DMSO) for subcutaneous administration. Therefore, the vehicle-treated control group consisted of rabbits given an equal volume of DMSO without drug. In the DMSO-treated control group, the ET(50) assessed 18 hours after initiation of aortal occlusion was 18.84+/-3.19 minutes. In contrast, treatment with 100 mg/kg of SC-236 given 5 minutes after the start of occlusion prolonged the ET(50) of the group significantly to 30.04+/-3.55, an effect that was still evident 48 hours later. In addition, lower doses of the drug (10 and 50 mg/kg) also showed a trend for an increase in ET(50). SC-236 (100 mg/kg) did not significantly alter body temperature after a subcutaneous injection.


CONCLUSIONS
The present study suggests that COX-2 plays an important role in the ischemic cascade of events that translate into ischemia-induced behavioral deficits and furthermore that selective COX-2 inhibitors may be useful in the treatment of ischemic stroke to improve behavioral functions.
Lapchak
P A
PA
Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu
Araujo
D M
DM
Song
D
D
Zivin
J A
JA
D000818:Animals; D001011:Aorta; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020760:Spinal Cord Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology*; D016896:Treatment Outcome; D000096926:Benzenesulfonamides
D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D018696:Neuroprotective Agents; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides