Hershkowitz N, Rogawski M A
Neuronal Excitability Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892.
Mol Pharmacol. 1991 May;39(5):592-8.
The action of tetrahydroaminoacridine (THA), a centrally active cholinesterase inhibitor that may provide symptomatic benefit in Alzheimer's disease, was studied on responses to the excitatory amino acid N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons, using whole-cell voltage-clamp and single-channel recording techniques. THA produced a concentration-dependent block of NMDA-evoked inward current responses (IC50, 190 microM at -60 mV), without affecting responses to quisqualate or kainate. THA block of NMDA responses was voltage dependent and was nearly completely relieved at positive holding potentials. Analysis of the voltage dependency indicated that the THA binding site senses 56% of the transmembrane electrostatic field. In single-channel recordings from outside-out membrane patches, THA appeared to reduce the frequency and duration of NMDA-evoked single-channel currents, without affecting the single-channel amplitude. The effects of THA on NMDA responses occur at concentrations 1-2 orders of magnitude greater than the therapeutic serum concentrations and, therefore, blockade of NMDA receptor-mediated responses is unlikely to contribute to the putative therapeutic action of THA. However, because NMDA receptors may play a critical role in cognitive and memory function, THA has the potential to produce undesirable central nervous system side effects at high doses.
四氢氨基吖啶（THA）是一种中枢活性胆碱酯酶抑制剂，可能对阿尔茨海默病有症状改善作用。本研究采用全细胞电压钳和单通道记录技术，研究了THA对培养海马神经元中兴奋性氨基酸N-甲基-D-天冬氨酸（NMDA）反应的作用。THA对NMDA诱发的内向电流反应产生浓度依赖性阻断（在-60 mV时IC50为190 microM），而不影响对quisqualate或kainate的反应。THA对NMDA反应的阻断具有电压依赖性，在正的钳制电位下几乎完全解除。对电压依赖性的分析表明，THA结合位点感知跨膜静电场的56%。在外侧向外膜片的单通道记录中，THA似乎降低了NMDA诱发的单通道电流的频率和持续时间，而不影响单通道幅度。THA对NMDA反应的影响发生在比治疗血清浓度高1 - 2个数量级的浓度下，因此，NMDA受体介导反应的阻断不太可能有助于THA假定的治疗作用。然而，由于NMDA受体可能在认知和记忆功能中起关键作用，高剂量的THA有可能产生不良的中枢神经系统副作用。
