Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
B'SYS, Witterswil, Switzerland.
Epilepsia. 2018 Aug;59(8):1492-1506. doi: 10.1111/epi.14504. Epub 2018 Jun 28.
Pharmacoresistance is a problem affecting ∼30% of chronic epilepsy patients. An understanding of the mechanisms of pharmacoresistance requires a precise understanding of how antiepileptic drugs interact with their targets in control and epileptic tissue. Although the effects of (S)-licarbazepine (S-Lic) on sodium channel fast inactivation are well understood and have revealed maintained activity in epileptic tissue, it is not known how slow inactivation processes are affected by S-Lic in epilepsy.
We have used voltage clamp recordings in isolated dentate granule cells (DGCs) and cortical pyramidal neurons of control versus chronically epileptic rats (pilocarpine model of epilepsy) and in DGCs isolated from hippocampal specimens from temporal lobe epilepsy patients to examine S-Lic effects on sodium channel slow inactivation.
S-Lic effects on entry into and recovery from slow inactivation were negligible, even at high concentrations of S-Lic (300 μmol/L). Much more pronounced S-Lic effects were observed on the voltage dependence of slow inactivation, with significant effects at 100 μmol/L S-Lic in DGCs from control and epileptic rats or temporal lobe epilepsy patients. For none of these effects of S-Lic could we observe significant differences either between sham-control and epileptic rats, or between human DGCs and the two animal groups. S-Lic was similarly effective in cortical pyramidal neurons from sham-control and epileptic rats. Finally, we show in expression systems that S-Lic effects on slow inactivation voltage dependence are only observed in Na 1.2 and Na 1.6 subunits, but not in Na 1.1 and Na 1.3 subunits.
From these data, we conclude that a major mechanism of action of S-Lic is an effect on slow inactivation, primarily through effects on slow inactivation voltage dependence of Na 1.2 and Na 1.6 channels. Second, we demonstrate that this main effect of S-Lic is maintained in both experimental and human epilepsy and applies to principal neurons of different brain areas.
抗药性是影响约 30%慢性癫痫患者的问题。了解抗药性的机制需要精确了解抗癫痫药物如何与控制和癫痫组织中的靶点相互作用。尽管 (S)-licarbazepine (S-Lic) 对钠通道快速失活的影响众所周知，并揭示了癫痫组织中的持续活性，但尚不清楚 S-Lic 如何影响癫痫中的缓慢失活过程。
我们使用电压钳记录技术，在分离的齿状颗粒细胞 (DGCs) 和皮质锥体神经元中（匹罗卡品癫痫模型），以及在颞叶癫痫患者海马标本中分离的 DGCs 中，研究 S-Lic 对钠通道缓慢失活的影响。
S-Lic 对进入和恢复缓慢失活的影响可以忽略不计，即使在高浓度的 S-Lic（300μmol/L）下也是如此。在 DGCs 中，S-Lic 对缓慢失活的电压依赖性有更明显的影响，在 100μmol/L S-Lic 时，控制和癫痫大鼠或颞叶癫痫患者的 DGCs 中均有显著影响。对于 S-Lic 的这些影响，我们既不能在假控制和癫痫大鼠之间，也不能在人类 DGCs 和两个动物组之间观察到显著差异。S-Lic 在假控制和癫痫大鼠的皮质锥体神经元中同样有效。最后，我们在表达系统中表明，S-Lic 对缓慢失活电压依赖性的影响仅在 Na 1.2 和 Na 1.6 亚基中观察到，而在 Na 1.1 和 Na 1.3 亚基中则没有。
从这些数据中，我们得出结论，S-Lic 的主要作用机制是对缓慢失活的影响，主要通过对 Na 1.2 和 Na 1.6 通道的缓慢失活电压依赖性的影响。其次，我们证明 S-Lic 的这种主要作用在实验性和人类癫痫中都得到了维持，并且适用于不同脑区的主要神经元。
