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Acute and long-term effects of intracerebroventricular administration of α-ketoisocaproic acid on oxidative stress parameters and cognitive and noncognitive behaviors

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Abstract

Maple Syrup Urine Disease (MSUD) is biochemically characterized by elevated levels of leucine, isoleucine and valine, as well as their corresponding transaminated branched-chain α-keto acids in tissue and biological fluids. Neurological symptoms and cerebral abnormalities, whose mechanisms are still unknown, are typical of this metabolic disorder. In the present study, we evaluated the early effects (1 h after injection) and long-term effects (15 days after injection) of a single intracerebroventricular administration of α-ketoisocaproic acid (KIC) on oxidative stress parameters and cognitive and noncognitive behaviors. Our results showed that KIC induced early and long-term effects; we found an increase in TBARS levels, protein carbonyl content and DNA damage in the hippocampus, striatum and cerebral cortex both one hour and 15 days after KIC administration. Moreover, SOD activity increased in the hippocampus and striatum one hour after injection, whereas after 15 days, SOD activity decreased only in the striatum. On the other hand, KIC significantly decreased CAT activity in the striatum one hour after injection, but 15 days after KIC administration, we found a decrease in CAT activity in the hippocampus and striatum. Finally, we showed that long-term cognitive deficits follow the oxidative damage; KIC induced impaired habituation memory and long-term memory impairment. From the biochemical and behavioral findings, it we presume that KIC provokes oxidative damage, and the persistence of brain oxidative stress is associated with long-term memory impairment and prepulse inhibition.

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Acknowledgements

Laboratory of Bioenergetics (Brazil) is 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 Universidade do Extremo Sul Catarinense (UNESC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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  1. Luciane Taschetto and Giselli Scaini contributed equally to this work

Authors and Affiliations

  1. Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil

    Luciane Taschetto, Giselli Scaini & Emilio L. Streck

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

    Luciane Taschetto, Giselli Scaini & Emilio L. Streck

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

    Hugo G. Zapelini, Ândrea C. Ramos & Patrícia F. Schuck

  4. Laboratório de Biologia Celular e Molecular, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Giulia Strapazzon & Vanessa M. Andrade

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

    Gislaine Z. Réus & João Quevedo

  6. Laboratório de Neuroquímica, Instituto de Biofísica Carlos Chagas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Monique Michels, Felipe Dal-Pizzol & Gustavo C. Ferreira

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  1. Luciane Taschetto
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Taschetto, L., Scaini, G., Zapelini, H.G. et al. Acute and long-term effects of intracerebroventricular administration of α-ketoisocaproic acid on oxidative stress parameters and cognitive and noncognitive behaviors. Metab Brain Dis 32, 1507–1518 (2017). https://doi.org/10.1007/s11011-017-0035-z

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