PUBLICATION

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

Authors
Baraban, S.C., Dinday, M.T., and Hortopan, G.A.
ID
ZDB-PUB-130905-29
Date
2013
Source
Nature communications   4: 2410 (Journal)
Registered Authors
Baraban, Scott
Keywords
none
MeSH Terms
  • Animals
  • Anticonvulsants/pharmacology
  • Anticonvulsants/therapeutic use*
  • Benzimidazoles/pharmacology
  • Benzimidazoles/therapeutic use*
  • Bromides/pharmacology
  • Diazepam/pharmacology
  • Dioxolanes/pharmacology
  • Drug Evaluation, Preclinical*
  • Epilepsies, Myoclonic/drug therapy
  • Gene Expression Profiling
  • Mutation
  • NAV1.1 Voltage-Gated Sodium Channel/genetics
  • NAV1.1 Voltage-Gated Sodium Channel/metabolism*
  • Potassium Compounds/pharmacology
  • Seizures/drug therapy
  • Seizures/genetics
  • Valproic Acid/pharmacology
  • Voltage-Gated Sodium Channel beta-1 Subunit/genetics
  • Voltage-Gated Sodium Channel beta-1 Subunit/metabolism
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
24002024 Full text @ Nat. Commun.
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.

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Human Disease / Model
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