Chen J, Graham S, Moroni F, Simon R
Department of Neurology, University of California, San Francisco.
J Pharmacol Exp Ther. 1993 Nov;267(2):937-41.
N-methyl-D-aspartate receptor antagonists are potent neuroprotectants in experimental focal cerebral ischemia, but behavioral and neuropathologic changes seen with these drugs in rodent models may limit the clinical utility of these compounds. Glycine's modulation of N-methyl-D-aspartate channel function offers another pharmacologic approach to excitotoxicity in ischemia. The potent glycine antagonist 7 Chlorothiokynurenic acid (7-Cl-Thio-Kyna) was studied in a permanent middle cerebral artery occlusion stroke model in the rat. The compound was effective, in a dose-dependent manner, in attenuating infarct size when administered before or after permanent middle cerebral artery occlusion. Its activity was mainly due to glycine antagonism inasmuch as 5 Chlorothiokynurenic acid, a compound having other pharmacological activities in common with 7-CI-Thio-Kyna (for instance the radical scavenger action), was inactive in this model. 7-Cl-Thio-Kyna did not produce cytological changes similar to MK 801.
N-甲基-D-天冬氨酸受体拮抗剂在实验性局灶性脑缺血中是有效的神经保护剂，但在啮齿动物模型中使用这些药物时所观察到的行为和神经病理学变化可能会限制这些化合物的临床应用。甘氨酸对N-甲基-D-天冬氨酸通道功能的调节为缺血性兴奋毒性提供了另一种药理学方法。在大鼠永久性大脑中动脉闭塞性卒中模型中对强效甘氨酸拮抗剂7-氯硫代犬尿烯酸（7-Cl-Thio-Kyna）进行了研究。当在永久性大脑中动脉闭塞之前或之后给药时，该化合物以剂量依赖性方式有效减轻梗死面积。其活性主要归因于甘氨酸拮抗作用，因为5-氯硫代犬尿烯酸（一种与7-Cl-Thio-Kyna具有其他共同药理活性的化合物，例如自由基清除作用）在该模型中无活性。7-Cl-Thio-Kyna不会产生类似于MK 801的细胞学变化。
