Massieu L, Thedinga K H, McVey M, Fagg G E
CIBA-GEIGY Ltd, Pharmaceutical Research Division, Basel, Switzerland.
Neuroscience. 1993 Aug;55(4):883-92. doi: 10.1016/0306-4522(93)90305-y.
Injection of the N-methyl-D-aspartate receptor agonist, quinolinic acid, into the rat striatum in vivo results in the degeneration of cholinergic and GABAergic neurons, as determined seven days later using the marker enzymes, choline acetyltransferase and glutamate decarboxylase, respectively. Such damage was dose-dependently prevented by CGP 37849 or MK-801 (competitive and uncompetitive N-methyl-D-aspartate receptor antagonists, respectively) administered systemically or intrastriatally at the same time as quinolinic acid. The neuroprotective activity of CGP 37849 was associated with the D-enantiomer, CGP 40116 (ED50 7.5 mg/kg i.p.), which was approximately 1.5-fold and 3.5-fold more potent than the related compounds, D-CPPene and CGS 19755, respectively. CGP 37849 was a weaker neuroprotectant than MK-801 (ED50 0.8 mg/kg i.p) when administered systemically, but was dramatically more potent following coinjection with quinolinic acid (ED50's 0.2 and 117 nmol, respectively). When injected intrastriatally 0.5-2 h post-quinolinic acid, CGP 37849 was protective over the entire period studied, whereas MK-801 was less effective at all post-quinolinic acid injection times. The finding that CGP 37849 is neuroprotective when administered intrastriatally 1-2 h post-quinolinic acid supports the hypothesis that a period exists following excitotoxic insult in which neurons are not committed to die, and can be rescued by blockade of ongoing N-methyl-D-aspartate receptor activation. Competition studies indicated that, when coinjected with 100-400 nmol quinolinic acid into the striatum, CGP 37849 exhibited kinetics predicted of a competitive N-methyl-D-aspartate receptor antagonist (declining neuroprotective potency with increasing doses of agonist), whereas MK-801 displayed a complex picture, with weak protective activity at low doses of quinolinic acid. Following systemic administration, neither antagonist was markedly affected by the dose of excitotoxin. When given i.p. at up to 6 h post-quinolinic acid, CGP 37849 and MK-801 showed essentially identical profiles of post-insult protection; degeneration of cholinergic neurons was reduced significantly throughout the entire post-insult period, whereas GABAergic neurons were protected only when drugs were administered 2 h or earlier post-quinolinic acid. The data indicate that competitive and uncompetitive N-methyl-D-aspartate receptor antagonists are effective neuroprotectants in vivo, and that parameters such as drug lipophilicity or mechanism of action at the receptor do not impinge upon their properties as systemically active cerebroprotectants.
在体内向大鼠纹状体注射N-甲基-D-天冬氨酸受体激动剂喹啉酸，7天后分别使用标记酶胆碱乙酰转移酶和谷氨酸脱羧酶测定，结果导致胆碱能和γ-氨基丁酸能神经元变性。在注射喹啉酸的同时全身或纹状体内给予CGP 37849或MK-801（分别为竞争性和非竞争性N-甲基-D-天冬氨酸受体拮抗剂），这种损伤呈剂量依赖性地得到预防。CGP 37849的神经保护活性与D-对映体CGP 40116（腹腔注射半数有效量7.5mg/kg）有关，其效力分别比相关化合物D-CPPene和CGS 19755强约1.5倍和3.5倍。全身给药时，CGP 37849作为神经保护剂比MK-801（腹腔注射半数有效量0.8mg/kg）弱，但与喹啉酸联合注射时效力显著更强（半数有效量分别为0.2和117nmol）。在喹啉酸注射后0.5 - 2小时纹状体内注射时，CGP 37849在整个研究期间都具有保护作用，而MK-801在喹啉酸注射后的所有时间点效果都较差。在喹啉酸注射后1 - 2小时纹状体内注射CGP 37849具有神经保护作用这一发现支持了这样的假说：在兴奋性毒性损伤后存在一个时期，在此期间神经元并非注定死亡，并且可以通过阻断持续的N-甲基-D-天冬氨酸受体激活而被挽救。竞争性研究表明，当与100 - 400nmol喹啉酸一起注射到纹状体中时，CGP 37849表现出竞争性N-甲基-D-天冬氨酸受体拮抗剂所预测的动力学（随着激动剂剂量增加神经保护效力下降），而MK-801表现出复杂的情况，在低剂量喹啉酸时具有较弱的保护活性。全身给药后，两种拮抗剂均未受到兴奋性毒素剂量的显著影响。在喹啉酸注射后长达6小时腹腔注射时，CGP 37849和MK-801显示出基本相同的损伤后保护情况；胆碱能神经元的变性在整个损伤后时期都显著减少，而γ-氨基丁酸能神经元仅在喹啉酸注射后2小时或更早给药时得到保护。数据表明，竞争性和非竞争性N-甲基-D-天冬氨酸受体拮抗剂在体内是有效的神经保护剂，并且诸如药物亲脂性或在受体上的作用机制等参数并不影响它们作为全身活性脑保护剂的性质。
