Journal article
Metabolic Alterations Induced by a Seizure-Causing Sodium Channel Mutation and their Partial Normalization by Dietary α-Linolenic Acid in Drosophila
Neurochemical research, Vol.51(1), 51
01/20/2026
DOI: 10.1007/s11064-026-04673-2
PMID: 41557249
Abstract
Epilepsy is increasingly recognized as a disorder with prominent metabolic disturbances, but how defined epilepsy-causing mutations reshape metabolism under controlled genetic and environmental conditions remains poorly understood. Here, we used the Drosophila melanogaster gain-of-function voltage-gated sodium channel (VGSC) mutant para
, a well-established model of neuronal and behavioral hyperexcitability, to characterize whole-body metabolic alterations and their modulation by dietary supplementation with the ω-3 polyunsaturated fatty acid α-linolenic acid (ALA), which strongly and specifically suppresses para
seizure phenotypes. Adult wild-type and para
females were reared on control or ALA-supplemented diets, and 172 metabolites were quantified using GC-MS and LC-MS. The para
mutation induced broad metabolic alterations, including enhanced glycolysis, reduced tricarboxylic acid cycle and pentose phosphate pathway intermediates, and depletion of nicotinamide riboside and nicotinic acid adenine dinucleotide, suggesting metabolic stress, mitochondrial dysfunction, and impaired redox balance. Amino acid and nucleotide metabolism were extensively reorganized, with prominent changes in tryptophan pathways, as well as imbalances in purine and pyrimidine nucleotides and cyclic nucleotides (cAMP, cGMP). Levels of microbially derived short-chain fatty acids and indole derivatives were elevated, implicating altered gut-brain metabolic interactions. Dietary ALA partially normalized key metabolites, including succinate, 6-phosphogluconate, glycine, proline, and short-chain fatty acids, and increased N-methylnicotinamide, consistent with improved redox homeostasis and attenuated inflammation. These findings demonstrate that VGSC-driven hyperexcitability elicits coordinated metabolic and microbiota-related changes, and that ALA can mitigate these disturbances, highlighting testable metabolic targets for mechanism-based interventions in epilepsy.
Details
- Title: Subtitle
- Metabolic Alterations Induced by a Seizure-Causing Sodium Channel Mutation and their Partial Normalization by Dietary α-Linolenic Acid in Drosophila
- Creators
- Karina Kruth - University of IowaJunko Kasuya - University of IowaVictoria Hand - University of AlabamaAtulya Iyengar - University of AlabamaToshihiro Kitamoto - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Neurochemical research, Vol.51(1), 51
- DOI
- 10.1007/s11064-026-04673-2
- PMID
- 41557249
- NLM abbreviation
- Neurochem Res
- ISSN
- 0364-3190
- eISSN
- 1573-6903
- Publisher
- Springer
- Grant note
- R21 NS127364 / NINDS NIH HHS R21NS127364 / NIH HHS
- Language
- English
- Date published
- 01/20/2026
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Biology; Anesthesia; Neuroscience and Pharmacology
- Record Identifier
- 9985130218902771
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