Title | Focally perfused succinate potentiates brain metabolism in head injury patients. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Jalloh, 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 |
Journal | J Cereb Blood Flow Metab |
Volume | 37 |
Issue | 7 |
Pagination | 2626-2638 |
Date Published | 2017 Jul |
ISSN | 1559-7016 |
Keywords | Adolescent, 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. |
DOI | 10.1177/0271678X16672665 |
Alternate Journal | J. Cereb. Blood Flow Metab. |
Citation Key | 10.1177/0271678X16672665 |
PubMed ID | 27798266 |
PubMed Central ID | PMC5482384 |
Grant List | G0600986 / / 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 |