An unidentified yet notable modification on I_Na and I_K(DR) caused by ramelteon

Abstract

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+ (INa) and delayed‐rectifier K+ currents (IK (DR)) could be suppressed under RAM. The IC50 values of 8.7 and 2.9 μM, respectively. RAM also diminished the magnitude of window Na+ current (INa (W)) elicited by short ascending ramp voltage, with unchanged the overall steady‐state current–voltage relationship. The decaying time course of INa during a train of depolarizing pulses arose upon the exposure to RAM. The conditioning train protocol which blocked INa 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 (GH3) cells, INa 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 INa and IK (DR) caused by RAM besides the agonistic action on melatonin receptors, which could partially explain its anti‐seizure activity.