PUBLICATION
Clemizole and Trazodone are Effective Antiseizure Treatments in a Zebrafish Model of STXBP1 Disorder
- Authors
- Moog, M., Baraban, S.C.
- ID
- ZDB-PUB-220423-7
- Date
- 2022
- Source
- Epilepsia open 7(3): 504-511 (Journal)
- Registered Authors
- Baraban, Scott
- Keywords
- STXBP1, antiepileptic, electrophysiology, seizure, zebrafish
- MeSH Terms
-
- Animals
- Anticonvulsants/pharmacology
- Anticonvulsants/therapeutic use
- Benzimidazoles
- Disease Models, Animal
- Humans
- Larva
- Munc18 Proteins
- Seizures/drug therapy
- Trazodone*/therapeutic use
- Zebrafish*/genetics
- PubMed
- 35451230 Full text @ Epilepsia Open
Citation
Moog, M., Baraban, S.C. (2022) Clemizole and Trazodone are Effective Antiseizure Treatments in a Zebrafish Model of STXBP1 Disorder. Epilepsia open. 7(3):504-511.
Abstract
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 antiseizure medications approved for clinical use and two recently identified repurposed drugs with antiseizure activity. 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. 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. Clemizole and trazodone were previously 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping