The antiepileptic drug losigamone decreases the persistent Na+ current in rat hippocampal neurons
The antiepileptic drug losigamone decreases the persistent Na+ current in rat hippocampal neurons
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DOI：
10.1016/s0006-8993(01)02863-3
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发表时间：
2001-11-30
期刊：
影响因子：
2.9
通讯作者：
Heinemann, U
中科院分区：
文献类型：
--
作者：
Gebhardt, C;Breustedt, JM;Heinemann, U
四烯酸衍生物洛西甘酮是一种新的抗惊厥药物，其作用机制以前是未知的。该药物降低自发动作电位的频率，抑制神经元的重复放电。本研究验证了洛西甘酮抑制大鼠脑片和培养海马神经元持续Na+电流（I-NaP）的假设。用充满葡萄糖酸cs或CsF的移液管对幼年大鼠（P15-P25）神经元进行全细胞电压钳记录。在药物阻断K+和Ca2+电流后，通过施加从-70 mV到0 mV的缓慢去极化电压坡道显示I-NaP。将Losigamone （100- 200mum）溶解于DMSO（0.1%）中，通过浴涂或局部压敷。Losigamone诱导I-NaP在去极化膜电位处的振幅下降，这在培养的神经元中是可逆的。当河豚毒素（TTX）加入到培养液中时，I-cat被阻断，只留下残留的非特异性外向阳离子电流（I-cat）。在这些条件下，洛西甘酮对电压斜坡的反应没有明显影响。因此，losigamone不影响I-cat或诱导任何额外的电流。这些数据表明，losigamone通过减少I-NaP来降低神经元的兴奋性。(C) 2001 Elsevier Science B.V.版权所有
The tetronic acid derivative losigamone is a new anticonvulsant drug with a mechanism of action that was previously unknown. The drug decreases the frequency of spontaneous action potentials and suppresses repetitive firing of neurons. Here we tested the hypothesis that losigamone suppresses the persistent Na+ current (I-NaP) in hippocampal neurons of rat brain slices and in cultured hippocampal neurons. Whole-cell voltage clamp recordings from neurons of juvenile rats (P15-P25) were performed with pipettes filled with Cs-gluconate or CsF. After pharmacological block of K+ and Ca2+ currents I-NaP was revealed by applying slow depolarizing voltage ramps from -70 to 0 mV. Losigamone (100-200 muM) was dissolved in DMSO (0.1%) and was applied by bath application or local pressure application. Losigamone induced a decrease in amplitude of I-NaP at depolarized membrane potentials which was reversible in cultured neurons. When tetrodotoxin (TTX) was added to the bath, I-cat was blocked and only a residual non-specific outward cation current (I-cat) remained. Losigamone had no obvious effect on responses to voltage ramps under these conditions. Thus, losigamone did not affect I-cat or induce any additional currents. The data suggest that losigamone decreases neuronal excitability via a decrease in I-NaP. (C) 2001 Elsevier Science B.V. All rights reserved.