抗癲癇藥物對視丘下核神經元上回返性鈉通道電流之作用

Abstract

電壓依賴性鈉離子通道在動作電位的傳遞及神經的興奮性上扮演著很重要的角色，一旦興奮性發生異常便容易造成神經性疾病，例如癲癇(epilepsy)等等，癲癇是一種先天或後天因素所引起的慢性腦部疾病，其特徵是由於腦細胞過度放電所引起的反覆性發作，而鈉離子通道直接與細胞的興奮性有關，所以常成為抗癲癇藥物(antiepileptic drugs；AEDs)的治療標的。近來的研究發現當膜電位復極化時，不活化態鈉離子通道回復到休息態的過程中，可能發生回返性鈉離子電流，亦即該電流可於膜電位復極化時，提供一個額外的閾下電流，進而促使神經細胞去極化的產生，因此有利於高頻率快速地放電。常見的抗癲癇藥物如：carbamazepine、phenytoin及lamotrigine等，已被證實會緩慢地結合於鈉離子通道的快速不活化態，可以有效地抑制癲癇放電，而不會影響到正常的神經活性，因此，研究回返性鈉離子電流與這些抗癲癇藥物的關係，應該是一個很重要的課題。我們改變前置去極化的電位，由較低的電位(-50 mv)提升至較高的電位(+120 mV)，其回返性鈉離子電流的峰值仍然會再逐漸成長，而後在40 mV以上，趨於飽合，由此可推論當回返性鈉離子電流產生時，與之相關的分子機制有相當大的電壓依賴性變動，此一依賴性最有可能來自鈉離子通道的結構本身之變化。此外，低濃度的抗癲癇藥物例如phenytoin，對於回返性鈉離子電流就已有抑制效果，而這樣的濃度對暫時性鈉離子電流卻沒有明顯的影響，足見得抗癲癇藥物此時對於鈉離子通道的結合速率、親和力等可能都已發生改變，而這可能是由於鈉離子通道本身結構改變，進而造成藥物受體亦隨之變化其構型所造成的結果。

Epilepsy is a common neurological disorder characterized by paroxysmal and excessive neuronal discharges of the brain. Because voltage-gated Na+channels play a crucial role in cellularexcitability, the channel constituies a major therapeutic target of antiepilepticdrugs (AEDs). Recent studies indicate that resurgent Na+ currents could provide subthreshold currents during the repolarization of the membrane potential and therefore may contributetohigh-frequency neuronal discharge. Carbamazepine, phenytoin and lamotrigine are common antiepileptic medication in clinical practice, and all are potent inhibitors of Na+ currents by slow binding to the fast inactivated state of Na+channels. We have demonstrated that changes ofthe depolarizingprepulse from -50mV to +120mV would make larges and larges resurgent Na+ currents. The amplitude of the resurgent currents would then be saturarng with prepulse potentials ≧ 40 mV. Moreover, We found that low concentration of antiepileplic drugs, such as phenytoin, may show an evident inhibitory effect on the resurgent but not transient Na+ currents. It is likely that the Na+ channel undergoes significant conformational changes to generate the resurgent Na+ currents.