Pellegrini-Giampietro D E, Cozzi A, Moroni F
Department of Preclinical and Clinical Pharmacology Mario Aiazzi Mancini, University of Florence, Italy.
Neuroscience. 1994 Dec;63(3):701-9. doi: 10.1016/0306-4522(94)90516-9.
We examined whether 7-Cl-thio-kynurenate, a potent antagonist at the glycine site of the N-methyl-D-aspartate receptor which also inhibits lipid peroxidation, protected CA1 pyramidal cells following transient forebrain ischemia. Global ischemia was produced in anesthetized gerbils by 5 min bilateral carotid artery occlusion; hippocampal injury was assessed seven days later. 7-Cl-thio-kynurenate (100 mg/kg, i.p. x 5) dramatically attenuated ischemia-induced CA1 cell loss (from 95 +/- 1 to 7 +/- 3%): the protection was associated with a delayed and marked reduction in the animals' temperature. However, when the gerbils were maintained normothermic for at least 360 min, 7-Cl-thio-kynurenate still provided partial (54 +/- 11%) but significant protection. No protection was observed when a reduction in temperature with a time course similar to that caused by 7-Cl-thio-kynurenate was experimentally induced in saline-treated ischemic animals. In situ hybridization revealed that expression of NMDA-R1, a subunit of the N-methyl-D-aspartate receptor, was selectively reduced in CA1 seven days following global ischemia. In ischemic gerbils treated with 7-Cl-thio-kynurenate, protected CA1 cells were still able to express normal amounts of NMDA-R1 messenger RNA. Our results demonstrate that 7-Cl-thio-kynurenate, a glutamate receptor blocker possessing radical scavenger properties, is effective in reducing CA1 hippocampal damage following global ischemia in the gerbil. Since there is growing evidence that a positive feedback interaction between activation of glutamate receptors and free radical formation may be responsible for the generation of ischemic brain damage, drugs capable of interfering with both pathogenic mechanisms may be useful in preventing post-ischemic neuronal death.
我们研究了7-氯硫代犬尿烯酸（一种N-甲基-D-天冬氨酸受体甘氨酸位点的强效拮抗剂，也能抑制脂质过氧化）在短暂性前脑缺血后是否能保护CA1锥体细胞。通过双侧颈动脉闭塞5分钟在麻醉的沙鼠中产生全脑缺血；7天后评估海马损伤情况。7-氯硫代犬尿烯酸（100毫克/千克，腹腔注射×5次）显著减轻了缺血诱导的CA1细胞损失（从95±1%降至7±3%）：这种保护作用与动物体温的延迟和显著降低有关。然而，当沙鼠保持正常体温至少360分钟时，7-氯硫代犬尿烯酸仍能提供部分（54±11%）但显著的保护作用。在生理盐水处理的缺血动物中，实验性诱导出与7-氯硫代犬尿烯酸引起的类似时间进程的体温降低时，未观察到保护作用。原位杂交显示，全脑缺血7天后，CA1区N-甲基-D-天冬氨酸受体亚基NMDA-R1的表达选择性降低。在用7-氯硫代犬尿烯酸治疗的缺血沙鼠中，受保护的CA1细胞仍能表达正常量的NMDA-R1信使核糖核酸。我们的结果表明，7-氯硫代犬尿烯酸这种具有自由基清除特性的谷氨酸受体阻滞剂，在减轻沙鼠全脑缺血后的CA1海马损伤方面是有效的。由于越来越多的证据表明谷氨酸受体激活与自由基形成之间的正反馈相互作用可能是缺血性脑损伤产生的原因，能够干扰这两种致病机制的药物可能有助于预防缺血后神经元死亡。
