EVALUATION OF DELAYED TREATMENT OF FOCAL CEREBRAL-ISCHEMIA WITH 3 SELECTIVE KAPPA-OPIOID AGONISTS IN CATS

Background and Purpose The purpose of this study was to determine the therapeutic efficacy of three kappa-opioid agonists used for delayed treatment of experimental focal cerebral ischemia. Methods Forty halothane-anesthetized cats underwent permanent occlusion of the right intracranial internal carotid, middle cerebral, and anterior cerebral arteries via a transorbital, microsurgical approach. Six hours after occlusion, animals received a blinded bolus injection, and a subcutaneous osmotic pump was implanted to provide continuous release for 7 days. The injection and pump contained either saline or one of three kappa-agonists: dynorphin (1-13), U-50,488, or DuP E3800. Survival, neurological function, tissue damage, and brain weight were assessed. Results As a group, kappa-agonist-treated animals had higher survival (P<.02), less tissue damage (P<.02), and lower brain weight (P<.05) than saline controls. U-50,488 more effectively improved survival (P<.03) than dynorphin (P<.07) or E3800 (P<.07). Each of the three kappa compounds improved tissue damage (dynorphin, P<.02; U-50,488, P<.05; E3800, P<.05). Greater improvement in neurological function was seen after treatment with dynorphin (P<.05) than with U-50,488 (P<.6) or E3800 (P<.7). The only significant reduction in brain weight was seen after dynorphin treatment (P<.01). Conclusions Compounds that act at the kappa subclass of opiate receptors are effective in increasing survival, improving neurological function, and decreasing tissue damage and edema in a cat model of focal cerebral ischemia. The current study provides support for the benefits of treatment of acute cerebrovascular ischemia with kappa-opioid agonists. The agents may prove to be of superior clinical utility because of efficacy even when administered 6 hours after the onset of stroke.