Focally perfused succinate potentiates brain metabolism in head injury patients

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 2,3-13C2 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.