Drug repurposing for Dravet syndrome in scn1Lab^−/− mutant zebrafish

Abstract

SummaryDravet syndrome (DS) is a severe genetic epileptic encephalopathy with onset during the first year of life. Zebrafish models recapitulating human diseases are often used as drug discovery platforms, but also for drug repurposing testing. It was recently shown that pharmacological modulation of three serotonergic (5‐HT) receptors (5‐HT 1D, 5‐HT 2C, 5‐HT 2A) exerts antiseizure effects in a zebrafish scn1Lab −/− mutant model of DS. Using the zebrafish DS model, our aim was to examine the possibility of repurposing efavirenz (EFA), lisuride (LIS), and rizatriptan (RIZA), marketed medicines with a 5‐HT on‐ or off‐target profile, as antiepileptic drugs for DS. To examine whether these compounds have a broader antiseizure profile, they were tested in pentylenetetrazol and ethyl ketopentenoate (EKP) zebrafish models. Pharmacological effects were assessed by locomotor behavior, local field potential brain recordings, and bioluminescence. EFA was active in all models, whereas LIS was selectively active in the zebrafish DS model. Mainly, a poor response was observed to RIZA. Taken together, our preclinical results show that LIS could be a potential candidate for DS treatment. EFA was also active in the EKP model, characterized by a high level of treatment resistance, and hence these data are potentially important for future treatment of drug‐resistant epilepsy.

Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene

“…Interestingly, fenfluramine, which showed success in phase III trials for the management of Dravet syndrome, did not exhibit any activity in the equivalent rodent models, highlighting the utility of zebrafish for identifying and/or validating new drug leads. More recently, Sourbron et al [31] performed a drug-repurposing screen, by assessing the response of scn1lab −/− mutant larvae to three different drugs targeting the serotonergic system. In this preliminary study, lisuride (anti-parkinson's drug, 5-HT 2A , types 2 and 3 dopamine receptor agonist) emerged as a new drug candidate for Dravet syndrome patients.…”

Loss of glutamate transportereaat2aleads to aberrant neuronal excitability, recurrent epileptic seizures and hypoactivity

“…In fact, not only the recurrent spontaneous seizures of eaat2a -/mutants, but also the reduced interictal brain activity mirror observations in human patients; de novo mutations in the human orthologue EAAT2 cause lower residual brain activity and profound intellectual disability 18,19 . In recent years, pharmacological and genetic zebrafish models have been used to advance the understanding of epileptogenesis [28][29][30][50][51][52][53][54][55][56][57] . Many of these studies focus on the inhibitory system by either pharmacologically or genetically manipulating GABA receptors.…”

A zebrafish-centric approach to antiepileptic drug development

“…Seizures in scn1lab mutant larvae respond favorably to DS ‘standard of care’ AEDs valproate, benzodiazepines and stiripentol but are pharmaco-resistant to most other AEDs ( Baraban et al, 2013 ; Griffin et al, 2018 ; Griffin et al, 2019 ; Banerji et al, 2021 ; Dinday and Baraban, 2015 ; Griffin et al, 2017 ; Hong et al, 2016 ). Many of these phenotypes, including spontaneous epileptic phenotypes at behavioral and electrophysiological levels, were subsequently replicated by other laboratories using didy s552 / scn1lab , CRISPR-generated scn1lab or morpholino antisense scn1lab knockdown larval zebrafish ( Sourbron et al, 2017 ; Sourbron et al, 2016 ; Sourbron et al, 2019 ; Eimon et al, 2018 ; Weuring et al, 2020 ). These unique features recapitulate key clinical phenotypes and allow for high-throughput drug screening in larval zebrafish.…”