Cerebral Energy Metabolism in Injured and Uninjured Brain

Head Injury is the largest single cause of death in those aged under 45 years in the developed world. After the initial trauma, a number of processes can cause further damage to the brain. One of these factors is the inability of nerve cells (neurones) to make enough energy. This study investigates how neurones use different fuels after head injury, and how this differs from normal brain and other tissues such as muscle. By using a technique called microdialysis we can deliver different brain fuels (glucose, pyruvate, succinate) and track how the brain uses them by tagging each fuel with a form of heavy carbon (C13). We can also use a specialised form of MRI scan called phosphorus MR spectrocopy to measure how much energy is stored in the cells as a molecule called ATP. A better understanding of how the brain makes energy when it is injured can allow us to develop treatments for a variety of conditions including head injury.

This study aims to investigate derangements in cerebral energy metabolism following traumatic brain injury. While the concept of energy failure is well recognised as a mechanism of neuronal injury and ultimately poor clinical outcome, the specific abnormalities compared with normal metabolism remain unclear. We propose delivering specific 13C labelled substrates to the human brain following trauma using microdialysis, to sequentially interrogate the glycolytic pathway (glucose supplementation), the tricarboxcylic acid cycle (pyruvate supplementation) and oxidative phosphorylation (succinate supplementation). We will monitor the metabolic consequences using a combination of (1) microdialysis parameters (including the lactate/pyruvate ratio to determine the redox state of the cell), (2) high-resolution Nuclear Magnetic Resonance spectroscopy of the microdialysates to analyse the downstream metabolites and determine the positions of 13C-labelling within these molecules (to ascertain which biochemical pathways are functioning), and (3) in vivo 31P Magnetic Resonance Spectroscopy to assess energy status (phosphocreatine/inorganic phosphate ratio and phosphocreatine/adenosine triphosphate ratio) at a cellular level. In order to differentiate the consequences of injury from normal metabolism, we will carry out parallel microdialysis studies in uninjured human brain and muscle. Together, these studies will increase our understanding of metabolic impairment in the injured brain and determine whether supplementation of specific substrates can improve energy generation as a potential therapeutic avenue. This may ultimately lead to novel strategies to improve clinical outcome.