AUTHOR=Fischer Florian P. , Karge Robin A. , Koch Henner , Voigt Aaron , Weber Yvonne G. , Wolking Stefan 

TITLE=The fruit fly Drosophila melanogaster as a screening model for antiseizure medications

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1489888

DOI=10.3389/fphar.2024.1489888

ISSN=1663-9812

ABSTRACT=<sec><title>Objective</title><p>Resistance to antiseizure medications (ASMs) is a major challenge in the treatment of patients with epilepsy. Despite numerous newly marketed ASMs, the proportion of drug-resistant people with epilepsy has not significantly decreased over the years. Therefore, novel and innovative seizure models for preclinical drug screening are highly desirable. Here, we explore the efficacy of a broad spectrum of ASMs in suppressing seizure activity in two established <italic>Drosophila melanogaster</italic> bang-sensitive mutants. These mutants respond with seizures to mechanical stimulation, providing a promising platform for screening novel ASMs.</p></sec><sec><title>Methods</title><p>Seven frequently used ASMs (brivaracetam, cenobamate, lacosamide, lamotrigine, levetiracetam, phenytoin, and valproate) were administered to the bang-sensitive mutants <italic>easily shocked</italic><sup><italic>2F</italic></sup> (<italic>eas</italic><sup><italic>2F</italic></sup>) and <italic>paralytic</italic><sup><italic>bss1</italic></sup> (<italic>para</italic><sup><italic>bss1</italic></sup>). After 48 h of treatment, the flies were vortexed to induce mechanical stimulation. The seizure probability (i.e., ratio of seizing and non-seizing flies) as well as the seizure duration were analyzed.</p></sec><sec><title>Results</title><p>In case of <italic>eas</italic><sup><italic>2F</italic></sup> mutants, treatment with the sodium channel blockers phenytoin and lamotrigine resulted in a robust reduction of seizure probability, whereas flies treated with lacosamide showed a decrease in seizure duration. Treatment with valproate resulted in both a reduction in seizure probability and in seizure duration. In contrast, levetiracetam, brivaracetam and cenobamate had no effect on the bang-sensitive phenotype of <italic>eas</italic><sup><italic>2F</italic></sup> flies. In case of <italic>para</italic><sup><italic>bss1</italic></sup> flies, none of the tested medications significantly reduced seizure activity, supporting its role as a model of intractable epilepsy.</p></sec><sec><title>Significance</title><p>Our results show that particularly sodium channel blockers as well as valproate are effective in suppressing seizure activity in the bang-sensitive mutant <italic>eas</italic><sup><italic>2F</italic></sup>. These findings demonstrate the usability of <italic>Drosophila</italic> for screening drugs with antiseizure properties. Due to fewer ethical concerns, the short life cycle, and low maintenance costs, <italic>Drosophila</italic> might provide an attractive and innovative high-throughput model for the discovery of novel antiseizure compounds.</p></sec>