Vornov J J, Coyle J T
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.
J Neurochem. 1991 Mar;56(3):996-1006. doi: 10.1111/j.1471-4159.1991.tb02020.x.
In some animal models of ischemia, neuronal degeneration can be prevented by the selective antagonism of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype, suggesting that glutamate released during ischemia causes injury by activating NMDA receptors. The rat hippocampal slice preparation was used as an in vitro model to study the pharmacology of glutamate toxicity and investigate why NMDA receptors are critical in ischemic injury. Acute toxicity was assessed by quantifying the inhibition of protein synthesis, which we confirmed by autoradiography to be primarily neuronal. The effect of NMDA was prevented by the specific antagonists MK-801 and ketamine, as well as by the less selective antagonist kynurenic acid. The less selective antagonists kynurenic acid and 6,7-dinitroquinoxaline-2,3-dione antagonized the effects of quisqualate and NMDA. In contrast to previous observations with dissociated neurons in tissue culture, the toxicity of glutamate was unaffected by antagonists, regardless of the glutamate concentration, the duration of exposure, or the presence of magnesium. The high concentration of glutamate required to inhibit protein synthesis and the inability of receptor antagonists to block the effect of glutamate suggest that either glutamate acts through a non-receptor-mediated mechanism, or that the receptor-mediated nature of glutamate effects are masked in the slice preparation, perhaps by the glial uptake of glutamate. The altered physiology induced by ischemia must potentiate the neurotoxicity of glutamate, because we observed with a brain slice preparation that only high concentrations of glutamate caused neurotoxicity in the presence of oxygen and glucose and that these effects were not reversed by glutamate receptor antagonists.
在一些缺血动物模型中，通过选择性拮抗N-甲基-D-天冬氨酸（NMDA）谷氨酸受体亚型可预防神经元变性，这表明缺血期间释放的谷氨酸通过激活NMDA受体导致损伤。大鼠海马脑片制备物被用作体外模型来研究谷氨酸毒性的药理学，并探究为何NMDA受体在缺血性损伤中至关重要。通过量化蛋白质合成的抑制来评估急性毒性，我们通过放射自显影证实其主要为神经元性的。NMDA的作用可被特异性拮抗剂MK-801和氯胺酮以及选择性较低的拮抗剂犬尿喹啉酸阻断。选择性较低的拮抗剂犬尿喹啉酸和6,7-二硝基喹喔啉-2,3-二酮可拮抗quisqualate和NMDA的作用。与先前在组织培养中对解离神经元的观察结果相反，无论谷氨酸浓度、暴露持续时间或镁的存在情况如何，谷氨酸的毒性均不受拮抗剂影响。抑制蛋白质合成所需的高浓度谷氨酸以及受体拮抗剂无法阻断谷氨酸的作用表明，要么谷氨酸通过非受体介导机制起作用，要么谷氨酸作用的受体介导性质在脑片制备物中被掩盖，可能是由于胶质细胞对谷氨酸的摄取。缺血诱导的生理改变必定增强了谷氨酸的神经毒性，因为我们在脑片制备物中观察到，只有高浓度的谷氨酸在有氧和葡萄糖存在的情况下才会引起神经毒性，并且这些作用不会被谷氨酸受体拮抗剂逆转。
