Kawasaki H, Tancredi V, D'Arcangelo G, Avoli M
Research Group on Cell Biology of Excitable Tissues, Montreal Neurological Institute, Montreal, Quebec, Canada.
Brain Res. 1998 Oct 5;807(1-2):125-34. doi: 10.1016/s0006-8993(98)00785-9.
We used an in vitro slice preparation to study whether and how the anticonvulsant drug topiramate (TPM, 50-500 microM) modulates the excitability of rat subicular neurons that generate action potential bursts mainly caused by voltage-dependent, Na+-electrogenesis. Subiculum is a gating structure for outputs originating from the hippocampus proper, and thus it may play a role in limbic seizures. In 28/45 neurons, TPM induced a steady hyperpolarization of the resting membrane potential (RMP) that ranged between -2 and -16 mV and was associated with a 24-62% decrease of the apparent membrane input resistance. TPM also depressed the ability of these cells to generate action potential bursts in response to brief (5-150 ms) depolarizing pulses; such an effect was characterized by an increase in the amount of intracellular depolarizing current required for eliciting action potential bursts, and it also occurred when the TPM-induced steady hyperpolarization was compensated by injecting steady depolarizing current. In addition TPM reduced by approx. 50% the regular action potential firing elicited by prolonged (350-1000 ms) depolarizing pulses (n=15 of 27 neurons). Recovery of the TPM-induced changes was not seen during washout for periods of 20-80 min (n=7). Both the steady hyperpolarization of the RMP and the input resistance decrease elicited by TPM were markedly reduced by the GABAA receptor antagonists bicuculline methiodide (10 microM; n=6) or picrotoxin (100 microM; n=2); such an effect was associated with a reduction, but not with blockade of the depressant action exerted by TPM on burst generation. Our findings indicate that TPM reduces subicular cell excitability, and modifies bursting ability and repetitive firing properties. These effects may be ascribed to actions on voltage-gated, Na+ electrogenesis and GABAA receptors. We propose that these changes in excitability may all contribute to the anticonvulsant action of TPM in limbic seizures that occur in temporal lobe epilepsy patients.
我们采用体外脑片制备技术，研究抗惊厥药物托吡酯（TPM，50 - 500微摩尔）是否以及如何调节大鼠下托神经元的兴奋性，这些神经元产生的动作电位爆发主要由电压依赖性钠电流产生。下托是海马体输出的门控结构，因此可能在边缘系统癫痫发作中起作用。在45个神经元中的28个中，TPM诱导静息膜电位（RMP）稳定超极化，范围在 - 2至 - 16毫伏之间，同时表观膜输入电阻降低24 - 62%。TPM还抑制了这些细胞对短暂（5 - 150毫秒）去极化脉冲产生动作电位爆发的能力；这种效应的特征是引发动作电位爆发所需的细胞内去极化电流增加，并且当通过注入稳定的去极化电流补偿TPM诱导的稳定超极化时也会出现。此外，TPM使由延长（350 - 1000毫秒）去极化脉冲引发的常规动作电位发放减少约50%（27个神经元中的15个）。在20 - 80分钟的洗脱期内未观察到TPM诱导的变化恢复（n = 7）。TPM引起的RMP稳定超极化和输入电阻降低均被GABAA受体拮抗剂甲磺酸荷包牡丹碱（10微摩尔；n = 6）或印防己毒素（100微摩尔；n = 2）显著减弱；这种效应与TPM对爆发产生的抑制作用的减弱有关，但未完全阻断。我们的研究结果表明，TPM降低了下托细胞的兴奋性，并改变了爆发能力和重复放电特性。这些效应可能归因于对电压门控钠电流和GABAA受体的作用。我们提出，这些兴奋性变化可能都有助于TPM对颞叶癫痫患者发生的边缘系统癫痫发作的抗惊厥作用。
