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α-Keto Acids Accumulating in Maple Syrup Urine Disease Stimulate Lipid Peroxidation and Reduce Antioxidant Defences in Cerebral Cortex From Young Rats

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Abstract

Maple syrup urine disease (MSUD) is an inherited neurometabolic disorder caused by deficiency of branched-chain α-keto acid dehydrogenase complex activity which leads to tissue accumulation of the branched-chain α-keto acids (BCKAs) α-ketoisocaproic acid (KIC), α-ketoisovaleric acid (KIV) and α-keto-β-methylvaleric acid (KMV) and their respective amino acids. Neuropathologic findings characteristic of the disease are cerebral edema and atrophy, whose pathophysiology is poorly known. In the present study, we investigated the in vitro effect of BCKAs on various parameters of oxidative stress, namely chemiluminescence (CL), thiobarbituric acid–reactive substances (TBA-RS), total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR), and the activities of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) in cerebral cortex of 30-day-old rats. The major effects observed were with KIC, which significantly increased CL and TBA-RS measurements, decreased TRAP and TAR values, and markedly inhibited GPx activity. KMV and KIV increased CL and decreased TRAP and TAR values. In contrast, these compounds did not affect CAT and SOD activities. Taken together, it was shown that: the BCKAs studied stimulated lipid peroxidation and reduced the brain antioxidant defences, suggesting an increased production of free radicals. In case the in vitro effects here detected also occur in vivo in MSUD, it can be presumed that oxidative stress might contribute, at least in part, to the brain damage found in the affected patients.

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Raquel Bridi, César A. Braun, Giovanni K. Zorzi, Clóvis M. D. Wannmacher, Moacir Wajner & Carlos Severo Dutra-Filho

  2. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

  3. Departamento de Ciencias Químicas, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile

    Eduardo G. Lissi

  4. Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil

    Carlos Severo Dutra-Filho

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  1. Raquel Bridi
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  2. César A. Braun
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  3. Giovanni K. Zorzi
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Correspondence to Carlos Severo Dutra-Filho.

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Bridi, R., Braun, C.A., Zorzi, G.K. et al. α-Keto Acids Accumulating in Maple Syrup Urine Disease Stimulate Lipid Peroxidation and Reduce Antioxidant Defences in Cerebral Cortex From Young Rats. Metab Brain Dis 20, 155–167 (2005). https://doi.org/10.1007/s11011-005-4152-8

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  • DOI: https://doi.org/10.1007/s11011-005-4152-8

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