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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >NR2B subunit selective NMDA antagonists inhibit neurotoxic effect of alcohol-withdrawal in primary cultures of rat cortical neurones.
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NR2B subunit selective NMDA antagonists inhibit neurotoxic effect of alcohol-withdrawal in primary cultures of rat cortical neurones.

机译：NR2B亚基选择性NMDA拮抗剂在大鼠皮质神经元的原代培养物中抑制戒酒的神经毒性作用。

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摘要

N-Methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission is thought to play a central role in the development of alcohol dependence and this alteration is supposed to be due to a differential up-regulation of the NR2B type of subunits. In this work, we examined the effect of some known (CP-101,606; CI-1041 and Co-101,244) and novel indole-2-carboxamide derivative NR2B subunit selective NMDA receptor antagonists (SSNAs) (RG-13579 and RG-1103) on the neurotoxic effect of withdrawal in ethanol pre-treated cultures of rat cortical neurones. The extent of neurotoxicity was estimated by measuring the activity of lactate dehydrogenase (LDH) that was released into the culture medium during the 24h withdrawal period. Here, we demonstrate that NR2B SSNAs given in the course of the withdrawal potently reduced the LDH release in ethanol pre-treated cultures. One of our novel compound, RG-1103, proved to be more potent than the reference NR2B SSNAs tested in this work having similar potency as the most potent but non-subunit selective NMDA receptor antagonist dizocilpine (MK-801). Acamprosate, a currently used therapeutic drug for the treatment of alcoholism was also effective although only in high micromolar concentrations. According to these observations, NR2B SSNAs are potent inhibitors of ethanol-withdrawal-induced neurotoxicity and considering that these agents have acceptable side effect profiles, they could be promising therapeutic candidates in the pharmacotherapy for physical signs of acute alcohol-withdrawal and associated neuronal damage.
机译：N-甲基-D-天门冬氨酸（NMDA）受体介导的谷氨酸能神经传递被认为在酒精依赖的发展中起着核心作用，这种改变被认为是由于NR2B型亚基的差异上调引起的。在这项工作中，我们研究了某些已知药物（CP-101,606; CI-1041和Co-101,244）和新型吲哚-2-羧酰胺衍生物NR2B亚基选择性NMDA受体拮抗剂（SSNA）（RG-13579和RG-1103）的作用对戒断大鼠皮层神经元的乙醇预处理培养物中戒断的神经毒性作用。通过测量在停药24小时期间释放到培养基中的乳酸脱氢酶（LDH）的活性来估计神经毒性的程度。在这里，我们证明了在撤药过程中给予的NR2B SSNAs可以有效减少乙醇预处理培养物中LDH的释放。我们的新型化合物之一RG-1103被证明比这项工作中测试的参考NR2B SSNA更有效，其功效与最有效但非亚基选择性的NMDA受体拮抗剂二唑西平（MK-801）相似。尽管仅在高微摩尔浓度下，阿坎酸（Acamprosate），一种目前用于治疗酒精中毒的治疗药物也是有效的。根据这些观察结果，NR2B SSNAs是乙醇戒断诱发的神经毒性的有效抑制剂，考虑到这些药物具有可接受的副作用，它们可能是药物治疗中急性乙醇戒断和相关神经元损害的物理迹象的有希望的治疗候选者。

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