Chen H S, Wang Y F, Rayudu P V, Edgecomb P, Neill J C, Segal M M, Lipton S A, Jensen F E
CNS Research Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
Neuroscience. 1998 Oct;86(4):1121-32. doi: 10.1016/s0306-4522(98)00163-8.
The potential of most N-methyl-D-aspartate antagonists as neuroprotectants is limited by side effects. We previously reported that memantine is an open-channel N-methyl-D-aspartate blocker with a faster off-rate than many uncompetitive N-methyl-D-aspartate antagonists such as dizocilpine maleate. This parameter correlated with memantine's known clinical tolerability in humans with Parkinson's disease. Memantine is the only N-methyl-D-aspartate antagonist that has been used clinically for excitotoxic disorders at neuroprotective doses. Therefore, we wanted to investigate further the basis of its clinical efficacy, safety, and tolerability. Here we show for the first time for any clinically-tolerated N-methyl-D-aspartate antagonist that memantine significantly reduces infarct size when administered up to 2 h after induction of hypoxia/ischemia in immature and adult rats. We found that at neuroprotective concentrations memantine results in few adverse side effects. Compared to dizocilpine maleate, memantine displayed virtually no effects on Morris water maze performance or on neuronal vacuolation. At concentrations similar to those in brain following clinical administration, memantine (6-10 microM) did not attenuate long-term potentiation in hippocampal slices and substantially spared the N-methyl-D-aspartate component of excitatory postsynaptic currents, while dizocilpine maleate (6-10 microM) or D-2-amino-5-phosphovalerate (50 microM) completely blocked these phenomena. We suggest that the favorable kinetics of memantine interaction with N-methyl-D-aspartate channels may be partly responsible for its high index of therapeutic safety, and make memantine a candidate drug for use in many N-methyl-D-aspartate receptor-mediated human CNS disorders.
大多数N-甲基-D-天冬氨酸拮抗剂作为神经保护剂的潜力受到副作用的限制。我们先前报道美金刚是一种开放通道的N-甲基-D-天冬氨酸阻滞剂，其解离速率比许多非竞争性N-甲基-D-天冬氨酸拮抗剂（如马来酸氯氮平）更快。该参数与美金刚在帕金森病患者中已知的临床耐受性相关。美金刚是唯一一种已在神经保护剂量下用于兴奋性毒性疾病临床治疗的N-甲基-D-天冬氨酸拮抗剂。因此，我们想进一步研究其临床疗效、安全性和耐受性的基础。在此我们首次表明，对于任何临床耐受性的N-甲基-D-天冬氨酸拮抗剂，在未成熟和成年大鼠诱导缺氧/缺血后2小时内给予美金刚，可显著减小梗死面积。我们发现，在神经保护浓度下，美金刚几乎没有不良副作用。与马来酸氯氮平相比，美金刚对莫里斯水迷宫表现或神经元空泡化几乎没有影响。在与临床给药后脑内浓度相似的情况下，美金刚（6 - 10 microM）不会减弱海马切片中的长时程增强，并且基本上保留了兴奋性突触后电流的N-甲基-D-天冬氨酸成分，而马来酸氯氮平（6 - 10 microM）或D-2-氨基-5-磷酸戊酸（50 microM）则完全阻断了这些现象。我们认为美金刚与N-甲基-D-天冬氨酸通道相互作用的有利动力学可能部分解释了其高治疗安全性指数，并使美金刚成为用于许多N-甲基-D-天冬氨酸受体介导的人类中枢神经系统疾病的候选药物。
