Indistinguishable Synaptic Pharmacodynamics of the N-Methyl-D-Aspartate Receptor Channel Blockers Memantine and Ketamine
Indistinguishable Synaptic Pharmacodynamics of the N-Methyl-D-Aspartate Receptor Channel Blockers Memantine and Ketamine
复制标题
DOI：
10.1124/mol.113.089334
复制
发表时间：
2013-12-01
影响因子：
3.6
通讯作者：
Mennerick, Steven
中科院分区：
文献类型：
--
作者：
Emnett, Christine M.;Eisenman, Lawrence N.;Mennerick, Steven
美金刚胺和氯胺酮，N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）的电压和激活依赖性通道阻滞剂，最近在临床上重新受到关注。已经报道了这些阻断剂之间的稳态药效学差异，但尚不清楚这些化合物是否差异地影响动态生理信号。在这项研究中，我们探讨了非平衡条件下的突触传递在海马网络在分离培养和海马脑片。等摩尔美金刚胺和氯胺酮对以下指标的影响不可区分：稳态NMDA电流、NMDAR兴奋性突触后电流（EPSC）衰减动力学、重复刺激期间的渐进性EPSC抑制和突触外NMDAR抑制。美金刚的治疗药物功效和耐受性归因于快速动力学和强电压依赖性。然而，在药物存在下的脉冲去极化揭示了两种化合物的平衡的令人惊讶的缓慢和相似的时间过程，尽管美金刚产生了更突出的快速组分（62%对48%）的再平衡。模拟预测，低门控功效是阻滞缓慢的电压依赖性缓解的基础。这一预测得到了更快的电压依赖性阻滞剂再平衡与几个实验操作的门控功效的经验支持。兴奋性突触后电位样电压命令产生的药物差异，只有大，延长去极化不太可能达到生理。事实上，我们发现在自发网络活动或对海马脑片可塑性的急性影响方面，药物之间没有差异。尽管无法区分突触药效学，氯胺酮提供了显着更大的神经保护，从氧葡萄糖剥夺诱导的损伤，与极端去极化条件下，药物之间的生物物理差异变得可检测的想法一致。我们的结论是，尽管电压依赖性的细微差异，在生理活动，阻滞剂的药效学在很大程度上是难以区分的，在很大程度上电压无关。
Memantine and ketamine, voltage-and activation-dependent channel blockers of N-methyl-D-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62% versus 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage-dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. Excitatory postsynaptic potential-like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs becomes detectable. We conclude that despite subtle differences in voltage dependence, during physiologic activity, blocker pharmacodynamics are largely indistinguishable and largely voltage independent.