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Apoptotic signaling pathways induced by acute administration of branched-chain amino acids in an animal model of maple syrup urine disease

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Abstract

Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of the branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids leucine, isoleucine and valine, as well as their corresponding α-keto acids and α-hydroxy acids. The affected patients present severe neurological symptoms, such as coma and seizures, as well as edema and cerebral atrophy. Considering that the mechanisms of the neurological symptoms presented by MSUD patients are still poorly understood, in this study, protein levels of apoptotic factors are measured, such as Bcl-2, Bcl-xL, Bax, caspase-3 and −8 in hippocampus and cerebral cortex of rats submitted to acute administration of branched-chain amino acids during their development. The results in this study demonstrated that BCAA acute exposure during the early postnatal period did not significantly change Bcl-2, Bcl-xL, Bax and caspase-8 protein levels. However, the Bax/Bcl-2 ratio and procaspase-3 protein levels were decreased in hippocampus. On the other hand, acute administration of BCAA in 30-day-old rats increase in Bax/Bcl-2 ratio followed by an increased caspase-3 activity in cerebral cortex, whereas BCAA induces apoptosis in hippocampus through activation and cleavage of caspase-3 and −8 without changing the Bax/Bcl-2 ratio. In conclusion, the results suggest that apoptosis could be of pivotal importance in the developmental neurotoxic effects of BCAA. In addition, the current studies also suggest that multiple mechanisms may be involved in BCAA-induced apoptosis in the cerebral cortex and hippocampus.

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Acknowledgments

We thank the authors who have provided relevant clarification on their articles. Laboratory of Bioenergetics (Brazil) are one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (ELS), FAPESC (ELS), and UNESC (ELS). ELS is a 1D CNPq Research Fellow.

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    Authors and Affiliations

    1. Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, 88806-000, SC, Brazil

      Thais C. Vilela, Giselli Scaini, Camila B. Furlanetto & Emilio L. Streck

    2. Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil

      Thais C. Vilela, Giselli Scaini, Camila B. Furlanetto & Emilio L. Streck

    3. Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, Santa Catarina, Brazil

      Thais C. Vilela, Giselli Scaini, Camila B. Furlanetto & Emilio L. Streck

    4. Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

      Matheus A. B. Pasquali, João Paulo A. Santos, Daniel P. Gelain & José Cláudio F. Moreira

    5. Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

      Patrícia F. Schuck

    6. Laboratório de Neuroquímica, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

      Gustavo C. Ferreira

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    1. Thais C. Vilela
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    2. Giselli Scaini
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    3. Camila B. Furlanetto
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    8. Patrícia F. Schuck
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    Correspondence to Emilio L. Streck.

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    Thais C. Vilela and Giselli Scaini contributed equally to this work.

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    Vilela, T.C., Scaini, G., Furlanetto, C.B. et al. Apoptotic signaling pathways induced by acute administration of branched-chain amino acids in an animal model of maple syrup urine disease. Metab Brain Dis 32, 115–122 (2017). https://doi.org/10.1007/s11011-016-9892-0

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