Metabolomic and lipidomic profiling reveals convergent pathways in attention deficit hyperactivity disorder therapeutics: Insights from established and emerging treatments.
Bartosz Grzymala, Haraldur Þorsteinsson, Dagmar Þöll Halldórsdóttir, Hildur Sóley Sveinsdóttir, Brynja Rún Sævarsdóttir, William H J Norton, Matthew O Parker, Óttar Rolfsson, Karl Ægir Karlsson
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引用次数: 0
Abstract
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with unclear pathological mechanisms. ADHD is treated with both stimulant and nonstimulant medications, but their therapeutic mechanisms and impact on brain metabolites are not fully understood. This study employed an untargeted metabolomics approach with liquid chromatography mass spectrometry to investigate the pathogenesis of ADHD, as well as the effects of established and novel therapeutics. We characterized the metabolomic signatures of the adgrl3.1 mutant zebrafish ADHD model and examined the impact of methylphenidate, guanfacine, atomoxetine, and 5 novel putative therapeutics identified in a prior screen, including amlodipine. Our analysis revealed that the drugs commonly affect pathways related to amino acid and lipid metabolism, specifically involving glycine, serine, threonine, phenylalanine, lysophosphatidylcholine, and sphingomyelin. This convergence on similar metabolic targets was unexpected and suggests a broader, systemic effect of ADHD therapeutics, challenging the traditional view of distinct drug mechanisms. Amlodipine exhibited metabolic effects consistent with established treatments, indicating its potential as a viable alternative or adjunct therapy. These findings provide new insights into the metabolic underpinnings of ADHD and highlight potential targets for developing improved therapeutic strategies. SIGNIFICANCE STATEMENT: This study explores the metabolic pathways affected by attention deficit hyperactivity disorder treatments using a zebrafish adgrl3.1 mutant model. Untargeted metabolomics revealed that both established and novel attention deficit hyperactivity disorder medications influence common amino acid and lipid metabolism pathways, suggesting systemic effects. Notably, amlodipine showed similar impacts as current drugs, offering promise as an alternative therapy.
期刊介绍:
A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.