Characterization of the interaction between fenamates and hippocampal neuron GABAA receptors
Characterization of the interaction between fenamates and hippocampal neuron GABAA receptors
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DOI：
10.1016/j.neuint.2007.04.017
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发表时间：
2007-11-01
影响因子：
4.2
通讯作者：
Halliwell, Robert E.
中科院分区：
文献类型：
--
作者：
Coyne, Leanne;Su, Jiping;Halliwell, Robert E.
Fenamate NSAID 具有多种重要作用，包括抗癫痫和神经保护作用。目前尚不清楚这些行为的根本机制。在这项研究中，研究了芬那酯 NSAID 组的五名成员对培养的大鼠海马神经元中表达的天然配体离子通道的影响。所有测试的芬那酯 (1-100 mu M) 剂量依赖性增强 GABA 诱发电流；甲芬那酸 (MFA) 是最有效的，并且被发现可以使 GABA 剂量反应曲线向左移动，而不影响最大幅度或 GABA 坡度。 NIFA 对 GABA 受体的调节在苯二氮卓类拮抗剂氟马西尼 (10 μM) 存在的情况下不会减弱，并且具有中度电压依赖性。在没有 GABA 的情况下，浓度 >= 10 RM 的 MFA 会引起剂量依赖性电流。这些电流通过地西泮 (1 RM) 增强并通过荷包牡丹碱 (10 μM) 阻断。 MFA (50 μM) 电流-电压关系和反转电位与 GABA 引起的相似。 MFA (1-100 mu M) 对次最大甘氨酸、谷氨酸或 NMDA 诱发电流没有影响。这些数据表明芬那酯 NSAID 是一类高效的 GABA(A) 受体调节剂和激活剂。 (C) 2007 Elsevier Ltd. 保留所有权利。
Fenamate NSAIDs have several central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligandgated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1-100 mu M) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose-response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by NIFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10 mu M) and was moderately voltage-dependent. MFA at concentrations >= 10 RM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1 RM) and blocked by bicuculline (10 mu M). The MFA (50 mu M) current-voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1-100 mu M) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA(A) receptor modulator and activators. (C) 2007 Elsevier Ltd. All rights reserved.