Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Epilepsy Res. 2011 Mar;94(1-2):75-85. doi: 10.1016/j.eplepsyres.2011.01.003.
Previous studies have demonstrated an increased risk of epilepsy in patients with Alzheimer's disease (AD). Also, in many mouse models of AD, animals have spontaneous seizures and frequent epileptiform discharges (EDs). Abnormal function of sodium channels has been proposed to contribute to hyperexcitability in a manner suggesting that drugs that block sodium channels might exacerbate the condition. Here we addressed this question by investigating whether common antiepileptic drugs (AEDs) that block sodium channels, including carbamazepine (CBZ), phenytoin (DPH), or valproic acid (VPA) have any effect on spontaneous seizures or EDs in APdE9 mice. Mice were successively treated with vehicle, followed by CBZ (10mg/kg, t.i.d.), DPH (10mg/kg, t.i.d.), or VPA (260 mg/kg, b.i.d.) for 3d. After wash-out and new vehicle treatment, higher doses of CBZ (40 mg/kg, t.i.d.), DPH (40 mg/kg, t.i.d.), or VPA (400mg/kg, b.i.d.) were administered for 3d (DPH) or 5d (CBZ, VPA). During the entire experiment, mice were under continuous (24/7) video-EEG monitoring. Our data show that each treatment reduced the number of spontaneous electrographic EDs. VPA was the most effective by reducing the ED frequency below 50% of that at baseline in 75% of mice. Western blot analysis of the Na(v)1.1 protein levels in the ventral temporal cortex and the hippocampus did not reveal any differences between the genotypes. Under the conditions tested, sodium channel blocking AEDs suppressed epileptiform activity in APdE9 mice with increased amyloid pathology. Whether this applies to other mouse models of AD with different APP mutations and/or genetic background remains to be explored.
先前的研究表明，阿尔茨海默病（AD）患者癫痫发作的风险增加。此外，在许多 AD 的小鼠模型中，动物会出现自发性癫痫发作和频繁的癫痫样放电（ED）。钠离子通道功能异常被认为是过度兴奋的原因之一，这表明阻断钠离子通道的药物可能会使病情恶化。在这里，我们通过研究是否阻断钠离子通道的常用抗癫痫药物（AEDs），包括卡马西平（CBZ）、苯妥英（DPH）或丙戊酸（VPA），对 APdE9 小鼠的自发性癫痫发作或 ED 有任何影响来解决这个问题。小鼠依次用载体、CBZ（10mg/kg，tid）、DPH（10mg/kg，tid）或 VPA（260mg/kg，bid）处理 3d。在洗脱和新的载体处理后，给予更高剂量的 CBZ（40mg/kg，tid）、DPH（40mg/kg，tid）或 VPA（400mg/kg，bid）治疗 3d（DPH）或 5d（CBZ、VPA）。在整个实验过程中，小鼠持续进行（24/7）视频-EEG 监测。我们的数据表明，每种治疗方法都减少了自发性脑电图 ED 的数量。VPA 通过将 ED 频率降低到基线的 50%以下，在 75%的小鼠中最为有效。腹侧颞叶皮质和海马的 Na（v）1.1 蛋白水平的 Western blot 分析未显示基因型之间存在任何差异。在测试的条件下，阻断钠离子通道的 AED 抑制了淀粉样蛋白病理增加的 APdE9 小鼠的癫痫样活动。这是否适用于具有不同 APP 突变和/或遗传背景的其他 AD 小鼠模型还有待探索。
