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.
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.