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α-Ketoadipic Acid and α-Aminoadipic Acid Cause Disturbance of Glutamatergic Neurotransmission and Induction of Oxidative Stress In Vitro in Brain of Adolescent Rats

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Abstract

Tissue accumulation of α-ketoadipic (KAA) and α-aminoadipic (AAA) acids is the biochemical hallmark of α-ketoadipic aciduria. This inborn error of metabolism is currently considered a biochemical phenotype with uncertain clinical significance. Considering that KAA and AAA are structurally similar to α-ketoglutarate and glutamate, respectively, we investigated the in vitro effects of these compounds on glutamatergic neurotransmission in the brain of adolescent rats. Bioenergetics and redox homeostasis were also investigated because they represent fundamental systems for brain development and functioning. We first observed that AAA significantly decreased glutamate uptake, whereas glutamate dehydrogenase activity was markedly inhibited by KAA in a competitive fashion. In addition, AAA and more markedly KAA induced generation of reactive oxygen and nitrogen species (increase of 2′,7′-dichloroflurescein (DCFH) oxidation and nitrite/nitrate levels), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione (GSH)) and aconitase activity. Furthermore, KAA-induced lipid peroxidation and GSH decrease were prevented by the antioxidants α-tocopherol, melatonin, and resveratrol, suggesting the involvement of reactive species in these effects. Noteworthy, the classical inhibitor of NMDA glutamate receptors MK-801 was not able to prevent KAA-induced and AAA-induced oxidative stress, determined by DCFH oxidation and GSH levels, making unlikely a secondary induction of oxidative stress through overstimulation of glutamate receptors. In contrast, KAA and AAA did not significantly change brain bioenergetic parameters. We speculate that disturbance of glutamatergic neurotransmission and redox homeostasis by KAA and AAA may play a role in those cases of α-ketoadipic aciduria that display neurological symptoms.

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Acknowledgements

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico #404883/2013-3, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul #2266-2551/14-2, Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul #PIBIC 27613, and Financiadora de Estudos e Projetos/Rede Instituto Brasileiro de Neurociência # 01.06.0842-00.

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  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Janaína Camacho da Silva, Alexandre Umpierrez Amaral, Cristiane Cecatto, Alessandro Wajner, Kálita dos Santos Godoy, Rafael Teixeira Ribeiro, Aline de Mello Gonçalves, Ângela Zanatta, Mateus Struecker da Rosa, Samanta Oliveira Loureiro, Guilhian Leipnitz, Diogo Onofre Gomes de Souza & Moacir Wajner

  2. Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Erechim, RS, Brazil

    Alexandre Umpierrez Amaral

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

    Carmen Regla Vargas & Moacir Wajner

  4. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Carmen Regla Vargas

  5. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600—Anexo, Porto Alegre, RS, CEP 90035-003, Brazil

    Guilhian Leipnitz, Diogo Onofre Gomes de Souza & Moacir Wajner

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da Silva, J.C., Amaral, A.U., Cecatto, C. et al. α-Ketoadipic Acid and α-Aminoadipic Acid Cause Disturbance of Glutamatergic Neurotransmission and Induction of Oxidative Stress In Vitro in Brain of Adolescent Rats. Neurotox Res 32, 276–290 (2017). https://doi.org/10.1007/s12640-017-9735-8

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