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The metabolic effect of α-ketoisocaproic acid: in vivo and in vitro studies

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Abstract

Maple syrup urine disease (MSUD) is characterized by a deficiency in the mitochondrial branched-chain α-keto acid dehydrogenase complex activity and, consequently, accumulation of the branched-chain amino acids and their respective branched-chain α-keto acids in fluids and the tissue. MSUD clinical symptoms include neurological alterations. KIC is considered one of the significant neurotoxic metabolites since its increased plasma concentrations are associated with neurological symptoms. We evaluated the effect of KIC intracerebroventricular (ICV) injection in hippocampal mitochondria function in rats. We also investigated the impact of KIC in cells’ metabolic activity (using MTT assay) and reactive species (RS) production in HT-22 cells. For this, thirty-day-old male rats were bilaterally ICV injected with KIC or aCSF. Thus, 1 hour after the administration, animals were euthanized, and the hippocampus was harvested for measured the activities of mitochondrial respiratory chain enzymes and RS production. Furthermore, HT-22 cells were incubated with KIC (1–10 mM) in 6, 12, and 24 h. Mitochondrial complexes activities were reduced, and the formation of RS was increased in the hippocampus of rats after KIC administration. Moreover, KIC reduced the cells’ metabolic ability to reduce MTT and increased RS production in hippocampal neurons. Impairment in hippocampal mitochondrial function seems to be involved in the neurotoxicity induced by KIC.

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Acknowledgements

The authors would like to thank Prof. Marcelo Farina for donate HT-22 cells. This research was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação De Aperfeiçoamento De Pessoal De Nível Superior (CAPES), Universidade do Extremo Sul Catarinense (UNESC), and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC).

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Authors and Affiliations

  1. Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil

    Hémelin R. Farias, Joice R. Gabriel, Maria Laura Cecconi, Isabela S. Lemos, Victoria L. de Rezende¹, Letícia B. Wessler, Mariane B. Duarte, Giselli Scaini & Emilio L. Streck

  2. Programa de Pós-graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 90035-000, Brazil

    Hémelin R. Farias & Jade de Oliveira

  3. Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Giselli Scaini

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  1. Hémelin R. Farias
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  2. Joice R. Gabriel
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  3. Maria Laura Cecconi
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  4. Isabela S. Lemos
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  5. Victoria L. de Rezende¹
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  10. Emilio L. Streck
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Correspondence to Emilio L. Streck.

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Farias, H.R., Gabriel, J.R., Cecconi, M.L. et al. The metabolic effect of α-ketoisocaproic acid: in vivo and in vitro studies. Metab Brain Dis 36, 185–192 (2021). https://doi.org/10.1007/s11011-020-00626-y

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