Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment

Scott C. Baraban (), Matthew T. Dinday and Gabriela A. Hortopan
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Scott C. Baraban: Epilepsy Research Laboratory, University of California, San Francisco, Box 0520, 513 Parnassus Avenue San Francisco, California 94143, USA
Matthew T. Dinday: Epilepsy Research Laboratory, University of California, San Francisco, Box 0520, 513 Parnassus Avenue San Francisco, California 94143, USA
Gabriela A. Hortopan: Epilepsy Research Laboratory, University of California, San Francisco, Box 0520, 513 Parnassus Avenue San Francisco, California 94143, USA

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: Abstract Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Nav1.1 (SCN1A), a voltage-gated sodium channel. Here we characterize zebrafish Nav1.1 (scn1Lab) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviours. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (~3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviours and electrographic seizures. This approach represents a new direction in modelling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder.

Date: 2013
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DOI: 10.1038/ncomms3410

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