Abstracts

Rationale: Resistance to antiseizure medications (ASMs) is one of the main challenges in the treatment of epilepsy patients. Despite the introduction of numerous new ASMs, the proportion of drug-resistant epilepsies has remained relatively unchanged over the years. Therefore, novel and innovative seizure models for preclinical drug screening are highly desirable. In this study, we investigate the efficacy of a wide range of old and new ASMs in suppressing seizures in Drosophila melanogaster bang-sensitive mutants. This established fly model exhibits seizures in response to mechanical shock, providing a promising platform for testing ASMs.

Methods: Seven ASMs (brivaracetam, cenobamate, lacosamide, lamotrigine, levetiracetam, phenytoin and valproate) were administered by feeding to the Drosophila bang-sensitive mutant easily shocked^2F (eas^2F), which carries a mutation in the gene encoding ethanolamine kinase. Upon 48 hours of treatment, the flies were vortexed to induce mechanical shock. The ratio of seizing and non-seizing flies as well as the seizure duration were examined.

Results: Treatment with the sodium channel blockers phenytoin and lamotrigine resulted in a strong 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 effects on the bang-sensitive phenotype of eas^2F flies.

Conclusions: Our results show that particularly sodium channel blockers as well as valproate are effective in suppressing seizures in the bang-sensitive mutant eas^2F. These findings further demonstrate the usability of Drosophila for assaying drugs with antiseizure properties. Next, the same ASMs will be tested in another bang-sensitive mutant (paralytic^bss1) that serves as a model for intractable epilepsy. Due its small size, fast generation time and low maintenance costs, Drosophila provides an attractive and innovative high-throughput model for the identification of novel antiseizure compounds.

Funding: German Research Foundation (WO 2385/2-1 to S.W.), DFG/FNR INTER Research Unit FOR2715 (WE 4896/4-1 and WE 4896/4-2 to Y.G.W.), Federal Ministry for Education and Research (Treat-ION, 01GM2210B to Y.G.W.)