Focally perfused succinate potentiates brain metabolism in head injury patients.
Howe, Duncan J
Shannon, Richard J
Gallagher, Clare N
Journal of Cerebral Blood Flow and Metabolism
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Jalloh, I., Helmy, A., Howe, D. J., Shannon, R. J., Grice, P., Mason, A., Gallagher, C. N., et al. (2017). Focally perfused succinate potentiates brain metabolism in head injury patients.. Journal of Cerebral Blood Flow and Metabolism, 37 (7), 2626-2638. https://doi.org/10.1177/0271678X16672665
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 2,3-13C2 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 13C-labelled metabolites (six patients). Metabolites 2,3-13C2 malate and 2,3-13C2 glutamine indicated tricarboxylic acid cycle metabolism, and 2,3-13C2 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 2,3-13C2 succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and 13C-labelling patterns in metabolites.
Traumatic brain injury (human), cerebral metabolism, microdialysis, nuclear magnetic resonance spectroscopy, succinate, 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
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External DOI: https://doi.org/10.1177/0271678X16672665
This record's URL: https://www.repository.cam.ac.uk/handle/1810/260924
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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