Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation
Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation
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DOI：
10.1016/s0306-4522(98)00163-8
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发表时间：
1998-10-01
期刊：
影响因子：
3.3
通讯作者：
Jensen, FE
中科院分区：
文献类型：
--
作者：
Chen, HSV;Wang, YF;Jensen, FE
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。我们以前报道，美金刚是一种开放通道的N-甲基-D-天冬氨酸受体阻滞剂，与许多非竞争性的N-甲基-D-天冬氨酸受体拮抗剂如马来酸地佐环平相比，其解离速率更快。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。美金刚是唯一的N-甲基-D-天冬氨酸拮抗剂，已被用于兴奋性神经毒性疾病的神经保护剂量的临床。因此，我们希望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，对于任何临床耐受的N-甲基-D-天冬氨酸拮抗剂，当在未成熟和成年大鼠中诱导缺氧/缺血后长达2小时给药时，美金刚显著降低梗死面积。我们发现，在神经保护浓度美金刚胺的结果很少有不良副作用。与马来酸地佐环平相比，美金刚对Morris水迷宫表现或神经元空泡化几乎没有影响。在与临床给药后大脑中的浓度相似的浓度下，美金刚胺（6-10 μ M）不减弱海马切片中的长时程增强，并且基本上不影响兴奋性突触后电流的N-甲基-D-天冬氨酸成分，而马来酸地佐环平（6-10 μ M）或D-2-氨基-5-磷酸戊酸（50 μ M）完全阻断了这些现象。天冬氨酸通道可能是其高治疗安全性指数的部分原因，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CNS疾病的候选药物。(C)1998年IBRO。出版社：Elsevier Science Ltd
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 significant ly 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 mu M) 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 mu M) or D-2-amino-5-phosphovalerate (50 mu M) 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. (C) 1998 IBRO. Published by Elsevier Science Ltd.