title: Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism.
abstract: Glutaric acidemia type I is an inherited metabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric and 3-hydroxyglutaric acids in the brain tissue of the affected patients. Considering that a toxic role was recently postulated for quinolinic acid in the neuropathology of glutaric acidemia type I, in the present work we investigated whether the combination of quinolinic acid with glutaric or 3-hydroxyglutaric acids or the mixture of glutaric plus 3-hydroxyglutaric acids could alter brain energy metabolism. The parameters evaluated in cerebral cortex from young rats were glucose utilization, lactate formation and (14)CO(2) production from labeled glucose and acetate, as well as the activities of pyruvate dehydrogenase and creatine kinase. We first observed that glutaric (5 mM), 3-hydroxyglutaric (1 mM) and quinolinic acids (0.1 microM) per se did not alter these parameters. Similarly, no change of these parameters occurred when combining glutaric with quinolinic acids or 3-hydroxyglutaric with quinolinic acids. In contrast, co-incubation of glutaric plus 3-hydroxyglutaric acids increased glucose utilization, decreased (14)CO(2) generation from glucose, inhibited pyruvate dehydrogenase activity as well as total and mitochondrial creatine kinase activities. The glutaric plus 3-hydroxyglutaric acids-induced inhibitory effects on creatine kinase were prevented by the antioxidants glutathione and catalase plus superoxide dismutase, indicating the participation of reactive oxygen species. Our data indicate a synergic action of glutaric and 3-hydroxyglutaric acids disturbing energy metabolism in cerebral cortex of young rats.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Anelise
authors.initials: A
authors.lastname: Tonin
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Viegas
authors.forename: Paula C
authors.initials: PC
authors.lastname: Ceolato
authors.forename: Alexandra
authors.initials: A
authors.lastname: Latini
authors.forename: Marcos L S
authors.initials: ML
authors.lastname: Perry
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Clóvis M D
authors.initials: CM
authors.lastname: Wannmacher
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Vargas
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D001928:Brain Diseases, Metabolic / Q000378:metabolism* / Q000503:physiopathology; D003402:Creatine Kinase / Q000378:metabolism; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism* / Q000633:toxicity; D019344:Lactic Acid / Q000378:metabolism; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000378:metabolism / Q000503:physiopathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D017378:Quinolinic Acid / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C108959:3-hydroxyglutaric acid; D000975:Antioxidants; D005977:Glutarates; D011768:Pyruvate Dehydrogenase Complex; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D003402:Creatine Kinase; D017378:Quinolinic Acid; C035736:glutaric acid; D005947:Glucose