Effects of a novel glutamate transporter blocker, (2S, 3S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy} aspartate (TFB-TBOA), on activities of hippocampal neurons
Effects of a novel glutamate transporter blocker, (2S, 3S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy} aspartate (TFB-TBOA), on activities of hippocampal neurons
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DOI：
10.1016/j.neuropharm.2004.11.006
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发表时间：
2005-03-01
影响因子：
4.7
通讯作者：
Ozawa, S
中科院分区：
文献类型：
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作者：
Tsukada, S;Iino, M;Ozawa, S
谷氨酸转运体迅速吸收突触释放的谷氨酸，并将突触间隙中的谷氨酸浓度维持在较低水平。(2S，3S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy}aspartate)是一种新型谷氨酸转运蛋白阻滞剂，能有效抑制神经胶质细胞转运蛋白的活性。TFB-TBOA对大鼠海马片辐射层星形胶质细胞突触激活转运体电流(STCs)的抑制作用呈剂量依赖性，IC50为13 nM，100 nM时约为对照组的10%。我们研究了TFB-TBOA对CA1区锥体细胞谷氨酸能突触传递和细胞兴奋性的影响。TFB-TBOA(100 NM)可延长N-甲基-D-天冬氨酸受体(NMDAR)介导的兴奋性突触后电流(EPSCs)的衰变，而仅当alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸受体(AMPAR)的脱敏作用被环噻嗪(CTZ)抑制时才能延长AMPAR介导的EPSCs的衰变。此外，长期应用TFB-TBOA可引起自发性癫痫样放电，并伴有膜电位持续去极化移动。这些癫痫样活动主要归因于NMDAR的激活。然而，即使在药物阻断NMDARs后，TFB-TBOA也通过在CTZ存在下激活AMPAR而引起类似的变化。因此，胶质转运蛋白对突触释放的谷氨酸的持续摄取对于保护海马神经元免受谷氨酸受体介导的过度兴奋是必不可少的。(C)2004爱思唯尔有限公司。保留所有权利。
Glutamate transporters rapidly take up synaptically released glutamate and maintain the glutamate concentration in the synaptic cleft at a low level. (2S, 3S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy}aspartate (TFB-TBOA) is a novel glutamate transporter blocker that potently suppresses the activity of glial transporters. TFB-TBOA inhibited synaptically activated transporter currents (STCs) in astrocytes in the stratum radiatum in rat hippocampal slices in a dose-dependent manner with an IC50 of 13 nM, and reduced them to approximately 10% of the control at 100 nM. We investigated the effects of TFB-TBOA on glutamatergic synaptic transmission and cell excitability in CA1 pyramidal cells. TFB-TBOA (100 nM) prolonged the decay of N-methyl-D-aspartic acid receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs), whereas it prolonged that of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated EPSCs only when the desensitization of AMPARs was reduced by cyclothiazide (CTZ). Furthermore, long-term application of TFB-TBOA induced spontaneous epileptiform discharges with a continuous depolarization shift of membrane potential. These epileptiform activities were mainly attributed to NMDAR activation. Even after pharmacological block of NMDARs, however, TFB-TBOA induced similar changes by activating AMPARs in the presence of CTZ. Thus, the continuous uptake of synaptically released glutamate by glial transporters is indispensable for protecting hippocampal neurons from glutamate receptor-mediated hyperexcitabilities. (c) 2004 Elsevier Ltd. All rights reserved.