title: Brain mitochondrial metabolic dysfunction and glutamate level reduction in the pilocarpine model of temporal lobe epilepsy in mice.
abstract: Although certain metabolic characteristics such as interictal glucose hypometabolism are well established for temporal lobe epilepsy (TLE), its pathogenesis still remains unclear. Here, we performed a comprehensive study of brain metabolism in a mouse model of TLE, induced by pilocarpine-status epilepticus (SE). To investigate glucose metabolism, we injected mice 3.5-4 weeks after SE with [1,2-(13)C]glucose before microwave fixation of the head. Using (1)H and (13)C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-pressure liquid chromatography, we quantified metabolites and (13)C labeling in extracts of cortex and hippocampal formation (HF). Hippocampal levels of glutamate, glutathione and alanine were decreased in pilocarpine-SE mice compared with controls. Moreover, the contents of N-acetyl aspartate, succinate and reduced nicotinamide adenine dinucleotide (phosphate) NAD(P)H were decreased in HF indicating impairment of mitochondrial function. In addition, the reduction in (13)C enrichment of hippocampal citrate and malate suggests decreased tricarboxylic acid (TCA) cycle turnover in this region. In cortex, we found reduced (13)C labeling of glutamate, glutamine and aspartate via the pyruvate carboxylation and pyruvate dehydrogenation pathways, suggesting slower turnover of these amino acids and/or the TCA cycle. In conclusion, mitochondrial metabolic dysfunction and altered amino-acid metabolism is found in both cortex and HF in this epilepsy model.
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Olav B
authors.initials: OB
authors.lastname: Smeland
authors.forename: Mussie G
authors.initials: MG
authors.lastname: Hadera
authors.forename: Tanya S
authors.initials: TS
authors.lastname: McDonald
authors.forename: Ursula
authors.initials: U
authors.lastname: Sonnewald
authors.forename: Karin
authors.initials: K
authors.lastname: Borges
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010862:Pilocarpine / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D018377:Neurotransmitter Agents; D010862:Pilocarpine; D018698:Glutamic Acid; D005947:Glucose