Faden A I, Shirane R, Chang L H, James T L, Lemke M, Weinstein P R
Department of Neurology, University of California, San Francisco.
J Pharmacol Exp Ther. 1990 Nov;255(2):451-8.
Opiate-receptor antagonists improve behavioral, electrophysiologic and/or histologic outcome in various experimental models of central nervous system ischemia. To address the potential mechanism(s) by which opiate-receptor antagonists may exert their protective actions in cerebral ischemia, metabolic and biochemical changes were measured in brain of rats pretreated with the opiate-receptor antagonist nalmefene or vehicle and subjected to 60 min of global ischemia followed by 2 hr of reperfusion. 31P and 1H magnetic resonance spectroscopy were used to follow the metabolic changes during ischemia and reperfusion, after which brain tissue was frozen in situ. Biochemical assays included free fatty acids, thromboxane B2, ascorbate, vitamin E and amino acids. Nalmefene-treated animals showed more rapid and complete recovery of cellular bioenergetic state (as indicated by the phosphocreatine to inorganic phosphate ratio), tissue acidosis and lactate levels during reperfusion than placebotreated controls. Ischemia/reperfusion caused significant increases of fatty free acids and thromboxane, associated with significant decreases of ascorbate and glutamate; nalmefene pretreatment limited each of these changes. The degree of metabolic improvement as reflected by recovery of high energy phosphates and reduction of lactic acidosis were highly correlated with changes in tissue levels of arachidonate and glutamate. Thus, the beneficial effects of opiate-receptor antagonists in cerebral ischemia may be due, in part, to an ability to enhance metabolic recovery with associated, reduction in phospholipid hydrolysis and excitotoxin release.
阿片受体拮抗剂可改善各种中枢神经系统缺血实验模型中的行为、电生理和/或组织学结果。为了探究阿片受体拮抗剂在脑缺血中发挥保护作用的潜在机制，我们对预先用阿片受体拮抗剂纳美芬或赋形剂处理的大鼠进行了实验，使其经历60分钟的全脑缺血，随后再灌注2小时，然后测量其大脑中的代谢和生化变化。利用磷-31和氢-1磁共振波谱来跟踪缺血和再灌注期间的代谢变化，之后将脑组织原位冷冻。生化检测包括游离脂肪酸、血栓素B2、抗坏血酸、维生素E和氨基酸。与接受安慰剂处理的对照组相比，接受纳美芬处理的动物在再灌注期间细胞生物能状态（以磷酸肌酸与无机磷酸盐的比率表示）、组织酸中毒和乳酸水平的恢复更快且更完全。缺血/再灌注导致游离脂肪酸和血栓素显著增加，同时抗坏血酸和谷氨酸显著减少；纳美芬预处理限制了这些变化中的每一种。高能磷酸盐的恢复和乳酸酸中毒的减轻所反映的代谢改善程度与花生四烯酸和谷氨酸组织水平的变化高度相关。因此，阿片受体拮抗剂在脑缺血中的有益作用可能部分归因于其增强代谢恢复的能力，以及相关的磷脂水解和兴奋性毒素释放的减少。
