A zebrafish-centric approach to antiepileptic drug development.
A zebrafish-centric approach to antiepileptic drug development.
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DOI：
10.1242/dmm.049080
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发表时间：
2021-07-01
影响因子：
4.3
通讯作者：
Baraban SC
中科院分区：
文献类型：
--
作者：
Baraban SC
斑马鱼（Danio rerio）是遗传和发育研究的有力实验模型。斑马鱼研究癫痫发作的适应性最初是使用常见的惊厥剂戊四唑（PTZ）建立的。幼年PTZ暴露斑马鱼表现出明确的行为惊厥和异常的电图活动，让人想起发作间期和发作癫痫样放电。通过使用这个模型，我们的实验室开发了简单的基于运动和电生理的测定，以监测和量化幼斑马鱼的癫痫发作。斑马鱼还为快速遗传操作和基于表型的高通量药物筛选提供了多种优势。将这些癫痫发作测定与代表Dravet综合征（一种罕见的遗传性癫痫）的转基因斑马鱼相结合，最终促成了超过3500种药物的基于表型的筛选。在这些斑马鱼筛选中发现的几种药物目前正在进行临床或同情使用试验。这种“从水族馆到床边”的方法的出现表明，更广泛的努力来适应和改进这种以斑马鱼为中心的策略可以推动各种令人兴奋的新发现。使用斑马鱼的筛选计划可以重塑抗癫痫药物发现的传统方法。在这里，我们描述的步骤，开发斑马鱼模型，代表人类癫痫，重点是斑马鱼模型的Dravet综合征。
Danio rerio (zebrafish) are a powerful experimental model for genetic and developmental studies. Adaptation of zebrafish to study seizures was initially established using the common convulsant agent pentylenetetrazole (PTZ). Larval PTZ-exposed zebrafish exhibit clear behavioral convulsions and abnormal electrographic activity, reminiscent of interictal and ictal epileptiform discharge. By using this model, our laboratory developed simple locomotion-based and electrophysiological assays to monitor and quantify seizures in larval zebrafish. Zebrafish also offer multiple advantages for rapid genetic manipulation and high-throughput phenotype-based drug screening. Combining these seizure assays with genetically modified zebrafish that represent Dravet syndrome, a rare genetic epilepsy, ultimately contributed to a phenotype-based screen of over 3500 drugs. Several drugs identified in these zebrafish screens are currently in clinical or compassionate-use trials. The emergence of this ‘aquarium-to-bedside’ approach suggests that broader efforts to adapt and improve upon this zebrafish-centric strategy can drive a variety of exciting new discoveries. Summary: Screening programs using zebrafish could reshape traditional approaches to antiepileptic drug discovery. Here we describe steps to develop zebrafish models that represent human epilepsies, with an emphasis on a zebrafish model of Dravet syndrome.
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影响因子：
2.2
作者：
Baraban, SC;Wenzel, HJ;Schwartzkroin, PA
通讯作者：
Schwartzkroin, PA
影响因子：
64.8
作者：
通讯作者：
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影响因子：
3
作者：
Chege, Sally W.;Hortopan, Gabriela A.;Baraban, Scott C.
通讯作者：
Baraban, Scott C.
影响因子：
4.8
作者：
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通讯作者：
Del Bene, Filippo
影响因子：
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作者：
Dana, Hod;Mohar, Boaz;Kim, Douglas S.
通讯作者：
Kim, Douglas S.