Taverna S, Sancini G, Mantegazza M, Franceschetti S, Avanzini G
Istituto Neurologico C. Besta, Milano, Italy.
J Pharmacol Exp Ther. 1999 Mar;288(3):960-8.
The actions of the antiepileptic drug topiramate (TPM) on Na+ currents were assessed using whole-cell patch-clamp recordings in dissociated neocortical neurons and intracellular recordings in neocortical slices. Relatively low TPM concentrations (25-30 microM) slightly inhibited the persistent fraction of Na+ current in dissociated neurons and reduced the Na+-dependent long-lasting action potential shoulders, which can be evoked in layer V pyramidal neurons after Ca++ and K+ current blockade. Conversely, the same drug concentrations were ineffective in reducing the amplitude of the fast Na+-dependent action potentials evoked in slices or the peak of transient Na+ (INaf) current evoked in isolated neurons from a physiological holding potential. Consistent INaf inhibition became, however, evident only when the neuronal membrane was kept depolarized to enhance resting Na+ channel inactivation. TPM (100 microM) was ineffective on the voltage dependence of activation but induced a leftward shift of the steady-state INaf inactivation curve. The drug-induced inhibitory effect increased with the duration of membrane depolarization, and the recovery of INaf after long membrane depolarizations was slightly delayed in comparison with that observed under control conditions. The obtained evidence suggests that the anticonvulsant action of TPM may operate by stabilizing channel inactivation, which can be induced by depolarizing events similar to those occurring in chronic epileptic conditions. Concurrently, the slight but significant inhibition of the persistent fraction of the Na+ current, obtained with the application of relatively low TPM concentrations, may contribute toward its anticonvulsant effectiveness by modulating the near-threshold depolarizing events that are sustained by this small current fraction.
使用全细胞膜片钳记录法在离体新皮质神经元中以及细胞内记录法在新皮质切片中评估了抗癫痫药物托吡酯（TPM）对钠离子电流的作用。相对较低浓度的TPM（25 - 30微摩尔）轻微抑制了离体神经元中钠离子电流的持续性部分，并减小了钠离子依赖性长时动作电位的波峰，该波峰可在钙离子和钾离子电流被阻断后在V层锥体神经元中诱发。相反，相同药物浓度在降低切片中诱发的快速钠离子依赖性动作电位的幅度或从生理钳制电位下分离的神经元中诱发的瞬时钠离子（INaf）电流的峰值方面无效。然而，只有当神经元膜保持去极化以增强静息钠离子通道失活时，INaf的持续抑制才变得明显。TPM（100微摩尔）对激活的电压依赖性无效，但导致稳态INaf失活曲线向左移位。药物诱导的抑制作用随着膜去极化的持续时间而增加，并且与对照条件下观察到的情况相比，长时间膜去极化后INaf的恢复略有延迟。所获得的证据表明，TPM的抗惊厥作用可能通过稳定通道失活来发挥作用，这种失活可由类似于慢性癫痫状态下发生的去极化事件诱导。同时，应用相对较低浓度的TPM所获得的对钠离子电流持续性部分的轻微但显著的抑制，可能通过调节由这一小部分电流维持的近阈值去极化事件，对其抗惊厥有效性做出贡献。
