Baskin D S, Widmayer M A, Browning J L, Heizer M L, Schmidt W K
Department of Surgery, Veterans Affairs Medical Center, Houston, Tex.
Stroke. 1994 Oct;25(10):2047-53; discussion 2054. doi: 10.1161/01.str.25.10.2047.
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.
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.
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).
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.
本研究旨在确定三种κ-阿片受体激动剂对实验性局灶性脑缺血延迟治疗的疗效。
40只经氟烷麻醉的猫通过经眶显微手术方法永久性闭塞右侧颅内颈内动脉、大脑中动脉和大脑前动脉。闭塞6小时后，动物接受盲法推注注射，并植入皮下渗透泵以持续释放7天。注射剂和泵中含有生理盐水或三种κ-激动剂之一：强啡肽（1-13）、U-50,488或DuP E3800。评估存活率、神经功能、组织损伤和脑重量。
作为一个整体，与生理盐水对照组相比，接受κ-激动剂治疗的动物存活率更高（P < 0.02）、组织损伤更少（P < 0.02）、脑重量更低（P < 0.05）。U-50,488在提高存活率方面比强啡肽（P < 0.07）或E3800（P < 0.07）更有效（P < 0.03）。三种κ化合物均改善了组织损伤（强啡肽，P < 0.02；U-50,488，P < 0.05；E3800，P < 0.05）。与U-50,488（P < 0.6）或E3800（P < 0.7）相比，强啡肽治疗后神经功能改善更明显（P < 0.05）。仅在强啡肽治疗后观察到脑重量有显著降低（P < 0.01）。
作用于阿片受体κ亚型的化合物在局灶性脑缺血猫模型中可有效提高存活率、改善神经功能并减少组织损伤和水肿。本研究为用κ-阿片受体激动剂治疗急性脑血管缺血的益处提供了支持。这些药物可能因其即使在中风发作6小时后给药仍有效而具有更高的临床应用价值。
