Modulation of AMPA receptors in spinal motor neurons by the neuroprotective agent riluzole
Modulation of AMPA receptors in spinal motor neurons by the neuroprotective agent riluzole
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DOI：
10.1002/jnr.20244
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发表时间：
2004-10-15
影响因子：
4.2
通讯作者：
Zona, C
中科院分区：
文献类型：
--
作者：
Albo, F;Pieri, M;Zona, C
采用全细胞膜片钳记录技术，研究治疗肌萎缩侧索硬化症(ALS)的药物利鲁唑与培养的小鼠脊髓运动神经元上α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)受体通道的相互作用。红藻氨酸在所有斑片细胞上均可引起浓度依赖的内向电流(EC50=35微米)。这些反应主要是通过激活AMPA受体介导的，而海人藻酸受体的作用可以忽略不计，因为浸浴100um的非竞争性AMPA受体拮抗剂GYK153655可以完全阻断海人藻酸诱导的电流。利鲁唑(0.5-100微米)可剂量依赖性地抑制红藻氨酸诱发的电流，其IC50为1.54微米，并且这种作用是可逆的。在所有被试的脊髓运动神经元中，当利鲁唑存在时，对红藻氨酸的反应降低，而不改变其EC50，这表明抑制机制是非竞争性的。在对照条件下和利鲁唑期间，红藻氨酸诱导的反应幅度与膜电位呈线性函数关系。在两种实验条件下，电流的反转电位无显著差异，但在1um利鲁唑存在下，100um红藻氨酸诱发的运动神经元总电导显著降低(P<；0.05)。这些结果揭示了利鲁唑与脊髓运动神经元谷氨酸能神经传递的相互作用，并有助于解释其在ALS治疗中的有利作用。(C)2004年Wiley-Liss公司
We investigated the interaction of riluzole, a therapeutic agent used in amyotrophic lateral sclerosis (ALS), with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse spinal motor neurons in culture using whole-cell patch-clamp recording techniques. Kainate elicited concentration-dependent (EC50 = 35 muM) inward currents in all the patched cells. These responses were mediated primarily through the activation of AMPA receptors with a negligible contribution from kainate receptors, because bath application of 100 muM GYK153655, a potent noncompetitive AMPA receptor antagonist, completely blocked the kainate-induced currents. Riluzole (0.5-100 muM) reduced in a dose-dependent manner the kainate-induced currents with an IC50 of 1.54 muM in all tested neurons (n = 25) and this effect was found to be reversible. The response to kainate decreased in the presence of 1 muM riluzole in all spinal motor neurons tested, without changing its EC50, indicating a noncompetitive mechanism of inhibition. The amplitude of the responses induced by kainate under control condition and during riluzole was a linear function of the membrane potential. The reversal potential of the current was not significantly different in the two experimental conditions, whereas the total conductance of the motor neurons for the currents induced by 100 muM kainate was reduced significantly in the presence of 1 muM riluzole (P < 0.05). These results reveal an interaction of riluzole with glutamatergic neurotransmission in spinal cord motor neurons and can contribute to explain its beneficial effect in the ALS treatment. (C) 2004 Wiley-Liss, Inc.