Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate

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Title: Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate
Authors: Gafson, AR
Savva, C
Thorne, T
David, MJ
Gomez-Romero, B
Lewis, M
Nicholas, R
Heslegrave, A
Zetterberg, H
Matthews, P
Item Type: Journal Article
Abstract: Objective To infer possible molecular effectors of therapeutic effects and adverse events for the pro-drug dimethyl fumarate (DMF, Tecfidera) in the plasma of relapsing-remitting MS patients (RRMS) based on untargeted blood plasma metabolomics. Methods Blood samples were collected from 27 RRMS patients at baseline and six weeks after initiation of treatment with DMF (BG-12; Tecfidera). Patients were separated into a discovery (n=15) and a validation cohort (n=12). Ten healthy controls were also recruited and blood samples were collected over the same time intervals. Untargeted metabolomic profiling using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was performed on plasma samples from the discovery cohort and healthy controls at Metabolon Inc. (Durham, NC). UPLC-MS was then performed on samples from the validation cohort at the National Phenome Centre (Imperial College, UK). Plasma neurofilament concentration (NfL) was also assayed for all subjects using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional statistical analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. Results In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine were increased 6-weeks after the start of treatment (q < 0.05). We confirmed that methyl succinyl carnitine was also increased in the validation cohort 6-weeks after the start of treatment (q < 0.05). Changes in concentrations of these metabolites were not seen over a similar time period in blood from the untreated healthy control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing, abdominal symptoms. The mean plasma NfL concentration before treatment was higher in the RRMS patients than in the healthy controls and reduced over the 15 months of treatment with DMF. Conclusion TCA cycle intermediates and metabolites are increased in RRMS patients treated with DMF and may mediate some effects of this pro-drug. The results suggest reversal of flux through the succinate dehydrogenase complex with pharmacological concentrations of fumarate. We hypothesise that contributions to both therapeutic effects and adverse events could be mediated through succinyl- carnitine ester agonism at hydroxylic acid receptor 2.
Issue Date: 1-May-2019
Date of Acceptance: 27-Feb-2019
ISSN: 2332-7812
Publisher: Lippincott, Williams & Wilkins
Journal / Book Title: Neurology, Neuroimmunology and Neuroinflammation
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: GlaxoSmithKline Services Unlimited
Medical Research Council (MRC)
Funder's Grant Number: COL011953
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Department of Medicine
Faculty of Medicine

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