Department of Neurological Surgery, Epilepsy Research Laboratory, University of California San Francisco , San Francisco, California 94143.
Department of Neurological Surgery, Epilepsy Research Laboratory, University of California San Francisco , San Francisco, California 94143 ; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco , San Francisco, California 94143.
eNeuro. 2015 Aug 31;2(4). doi: 10.1523/ENEURO.0068-15.2015. eCollection 2015 Jul-Aug.
Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS, including seizures, early fatality, and resistance to antiepileptic drugs. To discover new drug candidates for the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests that these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive, and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy.
电压门控钠离子通道（SCN1A）突变可导致 Dravet 综合征（DS），这是一种灾难性的儿童癫痫。具有 scn1Lab 突变的斑马鱼重现了与 DS 相关的显著表型，包括癫痫发作、早期死亡和对抗癫痫药物的耐药性。为了发现治疗 DS 的新药物候选物，我们筛选了一个约 1000 种化合物的化学文库，并鉴定出 4 种可挽救行为性癫痫成分的化合物，其中 1 种化合物（二甲噻嗪）可抑制相关的脑电图癫痫发作活动。芬氟拉明，而不是石杉碱甲，在我们的斑马鱼试验中也表现出抗癫痫活性。阻断神经元钙电流（二甲噻嗪）或增强血清素信号（芬氟拉明）的化合物在我们的斑马鱼模型中的有效性表明，这些化合物在 DS 患者中可能是重要的治疗靶点。还鉴定出了超过 150 种导致死亡的化合物。我们得出结论，行为和电生理测定的组合为基于表型的斑马鱼药物筛选提供了一种方便、敏感和快速的基础，模拟了一种遗传性癫痫。
