Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome
Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome
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DOI：
10.1093/brain/aww342
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发表时间：
2017-03-01
期刊：
影响因子：
14.5
通讯作者：
Baraban, Scott C.
中科院分区：
文献类型：
--
作者：
Griffin, Aliesha;Hamling, Kyla R.;Baraban, Scott C.
Dravet 综合征是一种灾难性的儿童癫痫症，具有早发性癫痫发作、语言和运动发育迟缓、睡眠障碍、焦虑样行为、严重认知缺陷和死亡风险增加。它主要是由编码神经元电压激活钠通道的 SCN1A 基因的从头突变引起的。 SCN1A 同源物发生突变的斑马鱼可以重现自发性癫痫发作活动，并模仿 Dravet 综合征中观察到的惊厥行为动作。在这里，我们展示了斑马鱼 scn1 突变体药物库的表型筛选可以快速并成功地识别新的治疗方法。我们证明克立咪唑与血清素受体结合，其抗癫痫活性可以通过作用于血清素信号通路的药物来模仿，例如：曲唑酮和氯卡色林。与这些斑马鱼的发现相一致，我们用临床批准的血清素受体激动剂（lorcaserin，Belviq (R)）治疗了五名医学上难以治愈的 Dravet 综合征患者，并观察到在癫痫发作频率和/或严重程度降低方面有一些有希望的结果。我们的研究结果证明了从斑马鱼的临床前发现到目标识别再到 Dravet 综合征的潜在临床治疗的快速途径。
Dravet syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics. We demonstrate that clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways e.g. trazodone and lorcaserin. Coincident with these zebrafish findings, we treated five medically intractable Dravet syndrome patients with a clinically-approved serotonin receptor agonist (lorcaserin, Belviq (R)) and observed some promising results in terms of reductions in seizure frequency and/or severity. Our findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet syndrome.