title: Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease.
abstract: Maple syrup urine disease is an inherited metabolic disorder characterized by tissue accumulation of branched-chain amino acids and their corresponding keto acids in the affected children. Although this disorder is predominantly characterized by neurological symptoms, only few studies were carried out to investigate its neuropathology. In this study we investigated the effect of the metabolites accumulating in maple syrup urine disease on the in vitro uptake of [3H]glutamate by synaptic vesicles of rat brain. Synaptic vesicle preparations from whole brain of male adult Wistar rats (200-250 g) were incubated with the branched-chain amino acids and their corresponding keto acids at final concentrations ranging from 0.25 to 10 mM for the determination of glutamate uptake. Glutamate uptake was significantly inhibited by L-leucine, L-isoleucine, L-2-ketoisocaproic acid and L-2-keto-3-methylvaleric acid by approximately 60%, whereas L-valine and L-2-ketoisovaleric acid showed no effect. We also verified that the metabolites probably act by competitive inhibition. Therefore, it is possible that extracellular glutamate levels may be increased in maple syrup urine disease and that excitotoxicity may be involved in the neuropathology of this disorder.
authors: Departamento de Bioquimica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 anexo, 90035-003 Porto, Alegre, RS, Brazil.
authors: R G
authors: RG
authors: Tavares
authors: C E
authors: CE
authors: Santos
authors: C I
authors: CI
authors: Tasca
authors: M
authors: M
authors: Wajner
authors: D O
authors: DO
authors: Souza
authors: C S
authors: CS
authors: Dutra-Filho
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism*; D045782:Hemiterpenes; D007532:Isoleucine / Q000378:metabolism / Q000494:pharmacology; D007651:Keto Acids / Q000378:metabolism / Q000494:pharmacology; D007930:Leucine / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008375:Maple Syrup Urine Disease / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014633:Valine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D045782:Hemiterpenes; D007651:Keto Acids; D007532:Isoleucine; C016211:alpha-keto-beta-methylvaleric acid; D018698:Glutamic Acid; C001505:alpha-ketoisovalerate; C013082:alpha-ketoisocaproic acid; D007930:Leucine; D014633:Valine