Broicher Tilman, Seidenbecher Thomas, Meuth Patrick, Munsch Thomas, Meuth Sven G, Kanyshkova Tatyana, Pape Hans-Christian, Budde Thomas
Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, Robert-Koch-Str. 27a, D-48149 Münster, Germany.
Neuropharmacology. 2007 Sep;53(3):431-46. doi: 10.1016/j.neuropharm.2007.05.030. Epub 2007 Jun 28.
Channel blocking, anti-oscillatory, and anti-epileptic effects of clinically used anti-absence substances (ethosuximide, valproate) and the T-type Ca2+ current (IT) blocker mibefradil were tested by analyzing membrane currents in acutely isolated local circuit interneurons and thalamocortical relay (TC) neurons, slow intrathalamic oscillations in brain slices, and spike and wave discharges (SWDs) occurring in vivo in Wistar Albino Glaxo rats from Rijswijk (WAG/Rij). Substance effects in vitro were compared between WAG/Rij and a non-epileptic control strain, the ACI rats. Ethosuximide (ETX) and valproate were found to block IT in acutely isolated thalamic neurons. Block of IT by therapeutically relevant ETX concentrations (0.25-0.75 mM) was stronger in WAG/Rij, although the maximal effect at saturating concentrations (>or=10 mM) was stronger in ACI. Ethosuximide delayed the onset of the low threshold Ca2+ spike (LTS) of neurons recorded in slice preparations. Mibefradil (>or=2 microM) completely blocked IT and the LTS, dampened evoked thalamic oscillations, and attenuated SWDs in vivo. Computational modeling demonstrated that the complete effect of ETX can be replicated by a sole reduction of IT. However, the necessary degree of IT reduction was not induced by therapeutically relevant ETX concentrations. A combined reduction of IT, the persistent sodium current, and the Ca2+ activated K+ current resulted in an LTS alteration resembling the experimental observations. In summary, these results support the hypothesis of IT reduction as part of the mechanism of action of anti-absence drugs and demonstrate the ability of a specific IT antagonist to attenuate rhythmic burst firing and SWDs.
通过分析急性分离的局部回路中间神经元和丘脑皮质中继（TC）神经元的膜电流、脑片中的丘脑内缓慢振荡以及来自荷兰莱顿的Wistar白化Glaxo大鼠（WAG/Rij）体内出现的棘波和慢波放电（SWD），测试了临床使用的抗失神药物（乙琥胺、丙戊酸盐）和T型Ca2+电流（IT）阻滞剂米贝拉地尔的通道阻断、抗振荡和抗癫痫作用。比较了WAG/Rij和非癫痫对照品系ACI大鼠体外物质的作用。发现乙琥胺（ETX）和丙戊酸盐可阻断急性分离的丘脑神经元中的IT。治疗相关ETX浓度（0.25 - 0.75 mM）对IT的阻断在WAG/Rij中更强，尽管饱和浓度（≥10 mM）时的最大效应在ACI中更强。乙琥胺延迟了切片制备中记录的神经元低阈值Ca2+尖峰（LTS）的起始。米贝拉地尔（≥2 μM）完全阻断IT和LTS，抑制诱发的丘脑振荡，并减弱体内的SWD。计算模型表明，ETX的完整效应可通过单纯降低IT来复制。然而，治疗相关的ETX浓度并未诱导出所需的IT降低程度。IT、持续性钠电流和Ca2+激活钾电流的联合降低导致LTS改变，类似于实验观察结果。总之，这些结果支持了降低IT作为抗失神药物作用机制一部分的假说，并证明了一种特异性IT拮抗剂减弱节律性爆发放电和SWD的能力。
