Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 37, Issue 7, Pages 2626-2638Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X16672665
Keywords
Traumatic brain injury (human); microdialysis; nuclear magnetic resonance spectroscopy; cerebral metabolism; succinate
Categories
Funding
- Medical Research Council [G0600986 ID79068, G1002277 ID98489]
- National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme
- Brain Injury and Repair Theme)
- National Institute for Health Research Biomedical Research Centre, Cambridge
- Canadian Institute of Health Research
- Medical Research Council/Royal College of Surgeons of England Clinical Research Training Fellowship [G0802251]
- Raymond and Beverly Sackler Fellowship
- National Institute for Health Research Senior Investigator Awards
- National Institute for Health Research Professorship
- Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship
- MRC [G1002277, G0001237, G9439390, G0600986, MC_U105663142] Funding Source: UKRI
- Medical Research Council [G1000183B, G0001237, G9439390, MC_U105663142, G0600986, G1002277] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10327, NIHR-RP-R3-12-013, NF-SI-0512-10090] Funding Source: researchfish
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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-C-13(2) succinate (12mmol/L) for 24h 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 C-13-labelled metabolites (six patients). Metabolites 2,3-C-13(2) malate and 2,3-C-13(2) glutamine indicated tricarboxylic acid cycle metabolism, and 2,3-C-13(2) 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-C-13(2) succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and C-13-labelling patterns in metabolites.
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