Wu Po-Ming, Tu Yi-Fang, Cho Hsin-Yen, Yu Meng-Cheng, Wu Yen-Hsien, Wu Sheng-Nan
Institute of Clinical Medicine, College of Medicine National Cheng Kung University Tainan Taiwan.
Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine National Cheng Kung University Tainan Taiwan.
FASEB Bioadv. 2024 Aug 28;6(10):442-453. doi: 10.1096/fba.2024-00008. eCollection 2024 Oct.
Despite advancement in anti-seizure medications, 30% of patients continue to experience recurrent seizures. Previous data indicated the antiepileptic properties of melatonin and its agonists in several animal models. However, the underlying mechanisms of melatonin and its agonists on cellular excitability remain poorly understood. In this study, we demonstrated the electrophysiological changes of two main kinds of ion channels that are responsible for hyperexcitability of neurons after introduction of melatonin agonists- ramelteon (RAM). In Neuro-2a cells, the amplitude of voltage-gated Na ( ) and delayed-rectifier K currents ( ) could be suppressed under RAM. The IC values of 8.7 and 2.9 μM, respectively. RAM also diminished the magnitude of window Na current ( ) elicited by short ascending ramp voltage, with unchanged the overall steady-state current-voltage relationship. The decaying time course of during a train of depolarizing pulses arose upon the exposure to RAM. The conditioning train protocol which blocked fitted the recovery time course into two exponential processes and increased the fast and slow time constant of recovery the presence of RAM. In pituitary tumor (GH) cells, amplitude was also effectively suppressed by the RAM. In addition, GH3-cells exposure to RAM decreased the firing frequency of spontaneous action potentials observed under current-clamp conditions. As a result, the RAM-mediated effect on INa was closely associated with its ability to decrease spontaneous action potentials. Collectively, we found the direct attenuation of and caused by RAM besides the agonistic action on melatonin receptors, which could partially explain its anti-seizure activity.
尽管抗癫痫药物有所进展，但仍有30%的患者继续经历癫痫复发。先前的数据表明褪黑素及其激动剂在几种动物模型中具有抗癫痫特性。然而，褪黑素及其激动剂对细胞兴奋性的潜在机制仍知之甚少。在本研究中，我们展示了在引入褪黑素激动剂雷美替胺（RAM）后，负责神经元过度兴奋的两种主要离子通道的电生理变化。在Neuro-2a细胞中，RAM可抑制电压门控钠电流（ ）和延迟整流钾电流（ ）的幅度。其IC值分别为8.7和2.9 μM。RAM还减小了短上升斜坡电压引发的窗钠电流（ ）的幅度，而整体稳态电流-电压关系未改变。在一系列去极化脉冲期间， 的衰减时间进程在暴露于RAM时出现。阻断 的条件刺激序列协议将恢复时间进程拟合为两个指数过程，并在存在RAM的情况下增加了快速和慢速恢复时间常数。在垂体肿瘤（GH）细胞中， 的幅度也被RAM有效抑制。此外，GH3细胞暴露于RAM会降低在电流钳条件下观察到的自发动作电位的发放频率。因此，RAM对 的介导作用与其降低自发动作电位的能力密切相关。总体而言，我们发现除了对褪黑素受体的激动作用外，RAM还直接减弱了 和 ，这可以部分解释其抗癫痫活性。
