Characterisation of impairments in glucose metabolism in models of neurological disease and treatments thereof
University of QLD.
Energy is needed to prevent brain damage and seizures. In the CNS most ATP is generated by oxidative metabolism of glucose. In this talk I will highlight biochemical techniques to study CNS glucose metabolism in rodent models of neurological disease. Data using 13C-glucose injection followed by subsequent quantification of 13C-glucose derived metabolites in CNS tissue will be shown. This can be coupled with studying maximal activities of enzymes involved in glycolysis and the Krebs cycle. Applying these techniques in a chronic epilepsy model, my laboratory found that entry of glucose-derived carbons into the Krebs cycle is impaired along with reductions in pyruvate dehydrogenase (PDH) activity in the epileptogenic hippocampus. This indicates that ATP generation in the epileptogenic hippocampus will be reduced, which likely contributes to seizure generation, as ATP is vital to keep neuronal membrane potentials stable and to regulate neuronal signalling. To improve ATP generation, treatments should be aimed at either increasing PDH activity or circumventing the need of PDH for ATP generation. Thus, fuels that can enter the CNS, such as ketones or medium chain fats are likely to decrease seizure generation. Promising data from a clinical trial with medium chain fats in people with epilepsy will be shown.