title: Kynurenines impair energy metabolism in rat cerebral cortex.
abstract: Growing evidence indicates that some metabolites derived from the kynurenine pathway, the major route of L-tryptophan catabolism, are involved in the neurotoxicity associated with several brain disorders, such as Huntington's disease, Parkinson's disease and Alzheimer's disease, as well as in glutaryl-CoA dehydrogenase deficiency (GAI). Considering that the pathophysiology of the brain damage in these neurodegenerative disorders is not completely defined, in the present study, we investigated the in vitro effect of L-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on some parameters of energy metabolism, namely glucose uptake, 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate, as well as on the activities of the respiratory chain complexes I-IV and Na+,K+-ATPase activity in cerebral cortex from 30-day-old rats. We observed that all compounds tested, except L-kynurenine, significantly increased glucose uptake and inhibited 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate. In addition, the activities of complexes I, II and IV of the respiratory chain were significantly inhibited by 3HK, while 3HA inhibited complexes I and II activities and AA inhibited complexes I-III activities. Moreover, Na+,K+-ATPase activity was not modified by these kynurenines. Taken together, our present data provide evidence that various kynurenine intermediates provoke impairment of brain energy metabolism.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600- Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Patrícia Fernanda
authors.initials: PF
authors.lastname: Schuck
authors.forename: Anelise
authors.initials: A
authors.lastname: Tonin
authors.forename: Gustavo
authors.initials: G
authors.lastname: da Costa Ferreira
authors.forename: Carolina Maso
authors.initials: CM
authors.lastname: Viegas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Latini
authors.forename: Clovis Milton
authors.initials: CM
authors.lastname: Duval Wannmacher
authors.forename: Angela Terezinha
authors.initials: AT
authors.lastname: de Souza Wyse
authors.forename: Carlos Severo
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000494:pharmacology; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D007736:Kynurenic Acid / Q000494:pharmacology; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D002245:Carbon Dioxide; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D007736:Kynurenic Acid; D005947:Glucose