Interrogating and potentiating energy metabolism in the human brain after traumatic brain injury
Hutchinson, Peter J
Carpenter, Keri L C
University of Cambridge
Doctor of Philosophy (PhD)
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Jalloh, I. (2018). Interrogating and potentiating energy metabolism in the human brain after traumatic brain injury (Doctoral thesis). https://doi.org/10.17863/CAM.20941
The pathophysiology of traumatic brain injury (TBI) includes perturbations to energy metabolism. Improving our understanding of cerebral energy metabolism will lead to strategies that improve clinical outcomes. For the studies in my thesis I used microdialysis to deliver carbon-13 labelled substrates to the human brain. I combined this with nuclear magnetic resonance (NMR) spectroscopy of interstitial fluid sampled from the brain to interrogate glucose, lactate and tricarboxylic acid (TCA) cycle metabolism. Study I: I defined the optimal parameters for quantitative proton and carbon-13 NMR of cerebral microdialysates. Study II: I measured baseline microdialysate metabolite concentrations for brain and muscle and investigated the influence of muscle activity and cerebral catheter placement in grey or white matter on metabolite concentrations. Study III: I used 1,2-13C2 glucose to measure glycolysis and pentose phosphate pathway activity. Glycolysis is the dominant lactate-producing pathway but the pentose phosphate pathway also contributes and is increased in some TBI patients. Study IV: I used arterio-venous gradients to measure glucose and lactate delivery to the brain. There are periods after injury when lactate is imported from the circulation despite relatively high brain lactate levels suggesting up-regulation of lactate transport. Study V: I followed the metabolism of 3-13C lactate and demonstrated that lactate is metabolised by the TCA cycle. This occurs in both normal and injured brain but not in muscle. Study VI: I used 2,3-13C2 succinate to investigate the role of the TCA cycle in producing metabolites that are exported into the interstitium. The TCA cycle is found to be a source of lactate. Succinate delivered to the brain improves redox and enhances glutamate uptake into cells. The implications of the findings in my thesis on existing knowledge of cerebral metabolism are discussed. Strategies that might potentiate cerebral metabolism and improve clinical outcomes are suggested.
Traumatic brain injury, Metabolism, nuclear magnetic resonance spectroscopy
Medical Research Council (Grant no. G1002277 ID 98489) and the National Institute for Health Research Biomedical Research Centre, Cambridge.
This record's DOI: https://doi.org/10.17863/CAM.20941
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