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. 2017 Jul;37(7):2626-2638.
doi: 10.1177/0271678X16672665. Epub 2016 Jan 1.

Focally perfused succinate potentiates brain metabolism in head injury patients

Ibrahim Jalloh  1 , Adel Helmy  1 , Duncan J Howe  2 , Richard J Shannon  1 , Peter Grice  2 , Andrew Mason  2 , Clare N Gallagher  1   3 , Matthew G Stovell  1 , Susan van der Heide  1 , Michael P Murphy  4 , John D Pickard  1   5 , David K Menon  5   6 , T Adrian Carpenter  5 , Peter J Hutchinson  1   5 , Keri Lh Carpenter  1   5
Affiliations

Focally perfused succinate potentiates brain metabolism in head injury patients

Ibrahim Jalloh et al. J Cereb Blood Flow Metab. 2017 Jul.

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.

Keywords: Traumatic brain injury (human); cerebral metabolism; microdialysis; nuclear magnetic resonance spectroscopy; succinate.

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Figures

Figure 1.
Figure 1.
Schematic of metabolism of 2,3-13C2 succinate via the TCA cycle and spin-out pathways. Blue-filled circles indicate 13C atoms. Red rectangular outlines indicate metabolites detected by 13C NMR in microdialysates. For further details, see Results and Discussion sections. ME: malic enzyme; PC: pyruvate carboxylase; PDH: pyruvate dehydrogenase; PEPCK: phosphoenolpyruvate carboxykinase; PK: pyruvate kinase.
Figure 2.
Figure 2.
Schematic of 13C-labelled microdialysis. Microdialysis is used both to deliver 13C-labelled succinate focally into the brain extracellular space and simultaneously collect those metabolite molecules that exit from the cells. Source: Adapted from Carpenter et al. ©2014 The Authors. Published by Elsevier B.V. Open access under a CC–BY licence.
Figure 3.
Figure 3.
ISCUS clinical microdialysis analyser measurements. Results are during 24 h baseline perfusion (with plain unsupplemented CNS perfusion fluid) and during 24 h perfusion with 2,3-13C2 succinate (disodium salt; 12 mmol/L). Symbols joined by lines represent individual patients (TBI Patients 1–9). Each pair of data-points indicates median levels at baseline and during succinate perfusion, respectively, for that patient. Note that, for Patients 6 and 7, the lactate concentrations were similar (but not identical), so their symbols and lines are very close to each other. For Patients 1 and 2, the baseline period was post-succinate, while for the other seven patients, the baseline period was pre-succinate. Changes between baseline and succinate perfusion were significant for lactate/pyruvate ratio (p = 0.0152), glucose (p = 0.038) and glutamate (p = 0.018) by Wilcoxon’s signed rank test.
Figure 4.
Figure 4.
Illustrative examples of 13C NMR spectra. Upper two spectra are for microdialysates from TBI Patients 3 and 5 who received perfusion with 2,3-13C2 succinate disodium salt (12 mmol/L). For comparison, the 2,3-13C2 succinate solution (before perfusion) (third spectrum) and microdialysate from an unlabelled TBI patient (using plain unsupplemented CNS perfusion fluid) (fourth spectrum) are also shown. Glc: glucose; Lac: lactate; Gln: glutamine; Mal: malate; DSS: 4,4-dimethyl-4-silapentane-1-sulfonate sodium salt (the internal reference standard). Spectra were run from −20 ppm to + 250 ppm. The main reference DSS signal at 0 ppm, and fumarate (138 ppm singlet for equivalent C2 and C3, in the spectra of patients with 2,3-13C2 succinate perfusion) are not shown in the ranges illustrated.
Figure 5.
Figure 5.
13C enrichment in glutamine and lactate. (a) Fractional enrichment values (%) for microdialysate 2,3-13C2 glutamine (blue bars; based on the glutamine C3 doublet signal) and 2,3-13C2 lactate (red bars; based on the lactate C3 doublet signal). (b) Corresponding concentrations (µmol/L) of 2,3-13C2 glutamine and 2,3-13C2 lactate.
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