Conventional and novel anti-seizure medications reveal a particular role for GABA A in a North Sea progressive myoclonus Epilepsy Drosophila model.

Autor: Polet SS; Department of Neurology, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands; Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands. Electronic address: s.s.polet@umcg.nl., de Koning TJ; Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands; Department of Neurology and Medical Genetics, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands; Department of Clinical Sciences, Pediatrics, Lund University, Lund BMC I12, 221 84, Sweden., Lambrechts RA; Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands; Department of Neurology, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands., Tijssen MAJ; Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands; Department of Neurology, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands., Sibon OCM; Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands; Department of Biomedical Sciences (BMS), University Medical Center Groningen, University of Groningen, 30.001 FB32, Groningen 9700 AD, the Netherlands., Gorter JA; Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, 30.001 AB51, Groningen 9700 RB, the Netherlands; Department of Biomedical Sciences (BMS), University Medical Center Groningen, University of Groningen, 30.001 FB32, Groningen 9700 AD, the Netherlands.
Jazyk: angličtina
Zdroj: Epilepsy research [Epilepsy Res] 2024 Jul; Vol. 203, pp. 107380. Date of Electronic Publication: 2024 May 14.
DOI: 10.1016/j.eplepsyres.2024.107380
Abstrakt: Objective: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3-5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model.
Method: A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls.
Results: As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well.
Conclusion: Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABA A receptors. This suggests that GABA A could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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