title: 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 2,3-13C2succinate (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 of13C-labelled metabolites (six patients). Metabolites 2,3-13C2malate and 2,3-13C2glutamine indicated tricarboxylic acid cycle metabolism, and 2,3-13C2lactate 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 2,3-13C2succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and13C-labelling patterns in metabolites.
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: Ibrahim
authors: I
authors: Jalloh
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: Adel
authors: A
authors: Helmy
authors: 2 Department of Chemistry, University of Cambridge, UK.
authors: Duncan J
authors: DJ
authors: Howe
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: Richard J
authors: RJ
authors: Shannon
authors: 2 Department of Chemistry, University of Cambridge, UK.
authors: Peter
authors: P
authors: Grice
authors: 2 Department of Chemistry, University of Cambridge, UK.
authors: Andrew
authors: A
authors: Mason
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.|4 Division of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Canada.
authors: Clare N
authors: CN
authors: Gallagher
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: Matthew G
authors: MG
authors: Stovell
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: Susan
authors: S
authors: van der Heide
authors: 5 MRC Mitochondrial Biology Unit, Cambridge, UK.
authors: Michael P
authors: MP
authors: Murphy
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.|3 Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: John D
authors: JD
authors: Pickard
authors: 3 Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, UK.|6 Division of Anaesthesia, Department of Medicine, University of Cambridge, UK.
authors: David K
authors: DK
authors: Menon
authors: 3 Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: T Adrian
authors: TA
authors: Carpenter
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.|3 Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: Peter J
authors: PJ
authors: Hutchinson
authors: 1 Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, UK.|3 Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, UK.
authors: Keri Lh
authors: KL
authors: Carpenter
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D019906:Nuclear Magnetic Resonance, Biomolecular; D010477:Perfusion; D013386:Succinates / Q000008:administration & dosage / Q000627:therapeutic use*; D015599:Trauma Severity Indices; D055815:Young Adult
chemical_list: D015415:Biomarkers; D013386:Succinates
keywords: Traumatic brain injury (human); cerebral metabolism; microdialysis; nuclear magnetic resonance spectroscopy; succinate