title: Alterations in Cytosolic and Mitochondrial [U-13C]Glucose Metabolism in a Chronic Epilepsy Mouse Model.
abstract: Temporal lobe epilepsy is a common form of adult epilepsy and shows high resistance to treatment. Increasing evidence has suggested that metabolic dysfunction contributes to the development of seizures, with previous studies indicating impairments in brain glucose metabolism. Here we aim to elucidate which pathways involved in glucose metabolism are impaired, by tracing the hippocampal metabolism of injected [U-13C]glucose (i.p.) during the chronic stage of the pilocarpine-status epilepticus mouse model of epilepsy. The enrichment of13C in the intermediates of glycolysis and the TCA cycle were quantified in hippocampal extracts using liquid chromatography-tandem mass spectroscopy, along with the measurement of the activities of enzymes in each pathway. We show that there is reduced incorporation of13C in the intermediates of glycolysis, with the percentage enrichment of all downstream intermediates being highly correlated with those of glucose 6-phosphate. Furthermore, the activities of all enzymes in this pathway including hexokinase and phosphofructokinase were unaltered, suggesting that glucose uptake is reduced in this model without further impairments in glycolysis itself. The key findings were 33% and 55% losses in the activities of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase, respectively, along with reduced13C enrichment in TCA cycle intermediates. This lower13C enrichment is best explained in part by the reduced enrichment in glycolytic intermediates, whereas the reduction of key TCA cycle enzyme activity indicates that TCA cycling is also impaired in the hippocampal formation. Together, these data suggest that multitarget approaches may be necessary to restore metabolism in the epileptic brain.
authors.affiliation: Department of Pharmacology, School of Biomedical Sciences, University of Queensland , St. Lucia, QLD 4072, Australia.
authors.forename: Tanya S
authors.initials: TS
authors.lastname: McDonald
authors.affiliation: Department of Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, QLD 4072, Australia; Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
authors.forename: Catalina
authors.initials: C
authors.lastname: Carrasco-Pozo
authors.affiliation: Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; Metabolomics Australia, Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Mark P
authors.identifier: 0000-0002-5436-1886
authors.initials: MP
authors.lastname: Hodson
authors.affiliation: Department of Pharmacology, School of Biomedical Sciences, University of Queensland , St. Lucia, QLD 4072, Australia.
authors.forename: Karin
authors.identifier: 0000-0001-7448-0770
authors.initials: K
authors.lastname: Borges
mesh_terms: D000818:Animals; D002247:Carbon Isotopes; D002908:Chronic Disease; D002952:Citric Acid Cycle / Q000502:physiology; D003600:Cytosol / Q000378:metabolism*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010862:Pilocarpine
chemical_list: D002247:Carbon Isotopes; D010862:Pilocarpine; D005947:Glucose
keywords: TCA cycle; glucose; glycolysis; metabolism; mitochondria; seizure