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Clemizole and Trazodone are Effective Antiseizure Treatments in a Zebrafish Model of STXBP1 Disorder

Maia Moog, View ORCID ProfileScott C. Baraban
doi: https://doi.org/10.1101/2022.01.30.478390
Maia Moog
aDepartment of Neurological Surgery & Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, USA
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Scott C. Baraban
aDepartment of Neurological Surgery & Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, USA
bHelen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA
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  • ORCID record for Scott C. Baraban
  • For correspondence: scott.baraban@ucsf.edu
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Abstract

Objective CRISPR-Cas9-generated zebrafish carrying a 12 base-pair deletion in stxbpb1b, a paralog sharing 79% amino acid sequence identity with human, exhibit spontaneous electrographic seizures during larval stages of development. Zebrafish stxbp1b mutants provide an efficient preclinical platform to test antiseizure therapeutics. The present study was designed to test prototype antiepileptic drugs approved for clinical use and two recently identified repurposed drugs with antiseizure activity.

Methods Larval homozygous stxbp1b zebrafish (4 days post-fertilization) were agarose-embedded and monitored for electrographic seizure activity using a local field recording electrode placed in midbrain. Frequency of ictal-like events was evaluated at baseline and following 45 min of continuous drug exposure (1 mM, bath application). Analysis was performed on coded files by an experimenter blinded to drug treatment and genotype.

Results Phenytoin, valproate, ethosuximide, levetiracetam, and diazepam had no effect on ictal-like event frequency in stxbp1b mutant zebrafish. Clemizole and trazodone decreased ictal-like event frequency in stxbp1b mutant zebrafish by 80% and 83%, respectively. These results suggest that repurposed drugs with serotonin receptor binding affinities could be effective antiseizure treatments.

Significance Clemizole and trazodone were identified in a larval zebrafish model for Dravet syndrome. Based primarily on these preclinical zebrafish studies, compassionate-use and double-blind clinical trials with both drugs have progressed. The present study extends this approach to a preclinical zebrafish model representing STXBP1-related disorders, and suggests that future clinical studies may be warranted.

Competing Interest Statement

S.C.B. is a co-Founder and Scientific Advisor for EpyGenix Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 30, 2022.
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Clemizole and Trazodone are Effective Antiseizure Treatments in a Zebrafish Model of STXBP1 Disorder
Maia Moog, Scott C. Baraban
bioRxiv 2022.01.30.478390; doi: https://doi.org/10.1101/2022.01.30.478390
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Clemizole and Trazodone are Effective Antiseizure Treatments in a Zebrafish Model of STXBP1 Disorder
Maia Moog, Scott C. Baraban
bioRxiv 2022.01.30.478390; doi: https://doi.org/10.1101/2022.01.30.478390

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