McDonald J W, Silverstein F S, Cardona D, Hudson C, Chen R, Johnston M V
Department of Pediatrics, Medical School, University of Michigan, Ann Arbor 48104.
Neuroscience. 1990;36(3):589-99. doi: 10.1016/0306-4522(90)90002-l.
MK-801, a non-competitive antagonist of N-methyl-D-aspartate-type glutamate receptors, was tested for its ability to antagonize excitotoxic actions of N-methyl-D-aspartate or quisqualic acid injected into the brains of seven-day-old rats. Stereotaxic injection of N-methyl-D-aspartate (25 nmol/0.5 microliters) or quisqualic acid (100 nmol/1.0 microliter) into the corpus striatum under ether anesthesia consistently produced severe unilateral neuronal necrosis in the basal ganglia, dorsal hippocampus and overlying neocortex. The distribution of the damage corresponded to the topography of glutamate receptors in the vulnerable regions demonstrated by previous autoradiographic studies. N-Methyl-D-aspartate produced severe, confluent neuronal destruction while quisqualic acid typically caused more selective neuronal necrosis. Intraperitoneal administration of MK-801 (0.1-1.0 mg/kg) 30 min before N-methyl-D-aspartate injection had a prominent dose-dependent neuroprotective effects as assessed morphometrically by comparison of bilateral striatal, hippocampal and cerebral hemisphere cross-sectional areas five days later. A 1 mg/kg dose of MK-801 given as pre-treatment completely protected the infant brain. The same dose of MK-801 was also completely protective when administered 30 or 40 min after N-methyl-D-aspartate and afforded partial protection when given 2 h later. MK-801 pre-treatment also prevented the electrically confirmed behavioral seizures induced by N-methyl-D-aspartate. The drug significantly reduced striatal but not hippocampal or neocortical injury when given as two doses (1 mg/kg) 30 min prior to and immediately following quisqualic acid injection. The data indicate that systemic administration of MK-801 can prevent N-methyl-D-aspartate-induced neuronal injury in perinatal rat brain even when administered after the initial insult. MK-801 also partially antagonized quisqualic acid-mediated neurotoxicity, suggesting that quisqualic acid-induced toxicity is, in part, mediated through N-methyl-D-aspartate receptor activation. The sensitivity of the developing brain to the toxicity of N-methyl-D-aspartate provides a sensitive and reproducible in vivo model for exploring these issues and for screening prospective neuroprotective drugs that act at the N-methyl-D-aspartate receptor-channel complex.
MK-801是一种N-甲基-D-天冬氨酸型谷氨酸受体的非竞争性拮抗剂，我们测试了它拮抗注入7日龄大鼠脑内的N-甲基-D-天冬氨酸或喹啉酸的兴奋毒性作用的能力。在乙醚麻醉下，将N-甲基-D-天冬氨酸（25纳摩尔/0.5微升）或喹啉酸（100纳摩尔/1.0微升）立体定向注射到纹状体中，在基底神经节、背侧海马和覆盖的新皮质中持续产生严重的单侧神经元坏死。损伤的分布与先前放射自显影研究显示的易损区域中谷氨酸受体的分布情况相符。N-甲基-D-天冬氨酸导致严重的、融合性的神经元破坏，而喹啉酸通常引起更具选择性的神经元坏死。在注射N-甲基-D-天冬氨酸前30分钟腹腔注射MK-801（0.1 - 1.0毫克/千克），五天后通过比较双侧纹状体、海马和大脑半球横截面积进行形态学评估，显示出显著的剂量依赖性神经保护作用。预处理剂量为1毫克/千克的MK-801完全保护了幼鼠大脑。当在注射N-甲基-D-天冬氨酸后30或40分钟给予相同剂量的MK-801时也具有完全保护作用，而在2小时后给予则提供部分保护。MK-801预处理还可预防由N-甲基-D-天冬氨酸诱发的经电证实的行为性癫痫发作。在注射喹啉酸前30分钟和注射后立即给予两剂（1毫克/千克）MK-801时，该药物显著减轻了纹状体损伤，但对海马或新皮质损伤无影响。数据表明，即使在初始损伤后给予MK-801，其全身给药也可预防围产期大鼠脑内N-甲基-D-天冬氨酸诱导的神经元损伤。MK-801也部分拮抗了喹啉酸介导的神经毒性，表明喹啉酸诱导的毒性部分是通过N-甲基-D-天冬氨酸受体激活介导的。发育中大脑对N-甲基-D-天冬氨酸毒性的敏感性为探索这些问题以及筛选作用于N-甲基-D-天冬氨酸受体通道复合物的潜在神经保护药物提供了一个敏感且可重复的体内模型。
