目的:北海进行性肌阵挛性癫痫(NS-PME)是一种罕见的以共济失调为特征的遗传性疾病,肌阵鸣和癫痫发作,病程进展。尽管NS-PME的原因是已知的,即GOSR2基因中的纯合突变(c.430G>T;p。Gly144Trp),缺乏足够的治疗。尽管平均3-5种抗癫痫药物(ASM)的组合,衰弱的肌阵鸣和癫痫持续存在。在这里,我们旨在通过评估NS-PME果蝇模型中ASM的个体作用来深入了解NS-PME中最有效的抗惊厥靶标。
方法:使用先前生成的NS-PME果蝇模型,显示进行性热敏癫痫发作。我们用这个模型来检验1。第一代ASM(巴比妥钠),2.NS-PME中使用的常见ASM(氯硝西泮,丙戊酸,左乙拉西坦,乙肟)和3。一种新型的第三代ASM(加奈索酮),其作用方式与巴比妥钠相似。通过将化合物以一定浓度范围添加到食物中来施用化合物。治疗7天后,测定热诱发癫痫发作的百分比,并与未治疗但受影响的对照组进行比较.
结果:如先前在NS-PME果蝇模型中报道的那样,巴比妥钠导致显著的癫痫发作抑制,在更高的剂量下增加效果。在通常规定的ASM中,氯硝西泮和乙肟导致显著的癫痫发作抑制,而丙戊酸和左乙拉西坦均未显示癫痫发作有任何变化.有趣的是,加奈索酮也能抑制癫痫发作。
结论:在测试的六种药物中,导致癫痫发作抑制的四项中的三项(巴比妥钠,氯硝西泮,加奈索酮)因其对GABAA受体的直接作用而闻名。这表明GABAA可能是治疗NS-PME的潜在重要靶标。因此,这些发现为探索加奈索酮在NS-PME和其他进行性肌阵挛性癫痫中的临床效果提供了依据。
OBJECTIVE: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3-5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model.
METHODS: A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls.
RESULTS: As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well.
CONCLUSIONS: Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABAA receptors. This suggests that GABAA could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.