Evaluation of delayed treatment of focal cerebral ischemia with three selective k-opioid agonists in cats

Background and Purpose: The purpose of this study was to determine the therapeutic efficacy of three κ-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 κ-agonists: dynorphin (1-13), U- 50,488, or DuP E3800. Survival, neurological function, tissue damage, and brain weight were assessed. Results: As a group, κ-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 κ 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 κ 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 κ-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.