Activation of kir 2.3 channel by tenidap suppress epileptiform burst discharges in cultured hippocampal neurons

Tenidap, a selective human Kir2.3 channel opener, has been reported to have antiepileptic.effect in the pilocarpine temporal lobe epilepsy rat model in our previous study. However, the effect of.tenidap on neurons and its relationship with the epileptiform bursting charges in neuron is still required.to be explored. In this study, cyclothiazide (CTZ) induced cultured hippocampal neuron epileptic model.was used to study the antiepileptic effect of tenidap and the relationship between Kir2.3 channel and the.neuronal epileptiform burst. Patch clamp recording showed that both acute (2h) and chronic (48h) CTZ.pre-treatment all significantly induced robust epileptiform burst activities in cultured hippocampal.neurons, and tenidap acutely application inhibited this highly synchronized abnormal activities. The.effect of tenidap is likely due to increased activity of Kir2.3 channels, since tenidap significantly.enhanced kir current recorded from those neurons. In addition, neurons overexpressing Kir2.3 channels,.by transfection with Kir2.3 plasmid, showed a significant large increase of the Kir current, prevented.CTZ treatment to induce epileptiform burst discharge. Our current study demonstrated that over.activation of Kir2.3 channel in hippocampal neurons could positively interference with epileptiform.burst activities, and tenidap, as a selective Kir2.3 channel opener, could be a potential candidate for.seizure therapy.

在我们之前的研究中，替尼达普（Tenidap）作为一种选择性的人类Kir2.3通道开放剂，据报道在毛果芸香碱颞叶癫痫大鼠模型中具有抗癫痫作用。然而，替尼达普对神经元的作用及其与神经元癫痫样放电的关系仍需探索。在本研究中，使用环噻嗪（CTZ）诱导的培养海马神经元癫痫模型来研究替尼达普的抗癫痫作用以及Kir2.3通道与神经元癫痫样放电之间的关系。膜片钳记录显示，急性（2小时）和慢性（48小时）CTZ预处理均显著诱导培养的海马神经元出现强烈的癫痫样放电活动，而急性应用替尼达普可抑制这种高度同步的异常活动。替尼达普的作用可能是由于Kir2.3通道活性增加，因为替尼达普显著增强了从这些神经元记录到的Kir电流。此外，通过转染Kir2.3质粒过表达Kir2.3通道的神经元，其Kir电流显著大幅增加，阻止了CTZ处理诱导癫痫样放电。我们目前的研究表明，海马神经元中Kir2.3通道的过度激活可对癫痫样放电活动产生积极的干扰，而替尼达普作为一种选择性的Kir2.3通道开放剂，可能是癫痫治疗的潜在候选药物。