Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome

Aliesha Griffin, Kyla R. Hamling, Kelly Knupp, Soon Gweon Hong, Luke P. Lee, Scott C. Baraban

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

Dravet syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics. We demonstrate that clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways e.g. trazodone and lorcaserin. Coincident with these zebrafish findings, we treated five medically intractable Dravet syndrome patients with a clinically-approved serotonin receptor agonist (lorcaserin, Belviq) and observed some promising results in terms of reductions in seizure frequency and/or severity. Our findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet syndrome.

Original languageEnglish
Pages (from-to)669-683
Number of pages15
JournalBrain
Volume140
Issue number3
DOIs
StatePublished - 1 Mar 2017

Bibliographical note

Publisher Copyright:
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Keywords

  • Drug-screening
  • Epilepsy
  • Personalized medicine
  • Serotonin
  • Zebrafish

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