Focally perfused succinate potentiates brain metabolism in head injury patients.

TitleFocally perfused succinate potentiates brain metabolism in head injury patients.
Publication TypeJournal Article
Year of Publication2017
AuthorsJalloh, I, Helmy, A, Howe, DJ, Shannon, RJ, Grice, P, Mason, A, Gallagher, CN, Stovell, MG, van der Heide, S, Murphy, MP, Pickard, JD, Menon, DK, T Carpenter, A, Hutchinson, PJ, Carpenter, KLh
JournalJ Cereb Blood Flow Metab
Volume37
Issue7
Pagination2626-2638
Date Published2017 Jul
ISSN1559-7016
KeywordsAdolescent, Adult, Biomarkers, Brain, Brain Chemistry, Brain Injuries, Traumatic, Citric Acid Cycle, Energy Metabolism, Female, Humans, Male, Microdialysis, Middle Aged, Nuclear Magnetic Resonance, Biomolecular, Perfusion, Succinates, Trauma Severity Indices, Young Adult
Abstract

Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3-(13)C2 succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of (13)C-labelled metabolites (six patients). Metabolites 2,3-(13)C2 malate and 2,3-(13)C2 glutamine indicated tricarboxylic acid cycle metabolism, and 2,3-(13)C2 lactate suggested tricarboxylic acid cycle spinout of pyruvate (by malic enzyme or phosphoenolpyruvate carboxykinase and pyruvate kinase), then lactate dehydrogenase-mediated conversion to lactate. Versus baseline, succinate perfusion significantly decreased lactate/pyruvate ratio (p = 0.015), mean difference -12%, due to increased pyruvate concentration (+17%); lactate changed little (-3%); concentrations decreased for glutamate (-43%) (p = 0.018) and glucose (-15%) (p = 0.038). Lower lactate/pyruvate ratio suggests better redox status: cytosolic NADH recycled to NAD(+) by mitochondrial shuttles (malate-aspartate and/or glycerol 3-phosphate), diminishing lactate dehydrogenase-mediated pyruvate-to-lactate conversion, and lowering glutamate. Glucose decrease suggests improved utilisation. Direct tricarboxylic acid cycle supplementation with 2,3-(13)C2 succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and (13)C-labelling patterns in metabolites.

DOI10.1177/0271678X16672665
Alternate JournalJ. Cereb. Blood Flow Metab.
Citation Key10.1177/0271678X16672665
PubMed ID27798266
PubMed Central IDPMC5482384
Grant ListG0600986 / / Medical Research Council / United Kingdom
G1002277 / / Medical Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom
NIHR-RP-R3-12-013 / / Department of Health / United Kingdom
G9439390 / / Medical Research Council / United Kingdom