title: Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment.
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.
authors.affiliation: 1] Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, San Francisco, Box 0520, 513 Parnassus Avenue San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Dinday
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Hortopan
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001965:Bromides / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004831:Epilepsies, Myoclonic / Q000188:drug therapy; D020869:Gene Expression Profiling; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D017680:Potassium Compounds / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology; D062547:Voltage-Gated Sodium Channel beta-1 Subunit / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D001562:Benzimidazoles; D001965:Bromides; D004148:Dioxolanes; D062550:NAV1.1 Voltage-Gated Sodium Channel; D017680:Potassium Compounds; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D029961:Zebrafish Proteins; C523645:scn1ba protein, zebrafish; C000605300:scn1laa protein, zebrafish; D014635:Valproic Acid; C039004:potassium bromide; D003975:Diazepam; C021092:stiripentol; C084582:clemizole