Neurotoxicity Research

, Volume 32, Issue 2, pp 276–290 | Cite as

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

  • 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
  • Carmen Regla Vargas
  • Guilhian Leipnitz
  • Diogo Onofre Gomes de Souza
  • Moacir Wajner
ORIGINAL ARTICLE

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.

Keywords

α-Ketoadipic aciduria α-Ketoadipic acid α-Aminoadipic acid Glutamatergic neurotransmission Redox homeostasis Bioenergetics 

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Janaína Camacho da Silva
    • 1
  • Alexandre Umpierrez Amaral
    • 1
    • 2
  • Cristiane Cecatto
    • 1
  • Alessandro Wajner
    • 1
  • Kálita dos Santos Godoy
    • 1
  • Rafael Teixeira Ribeiro
    • 1
  • Aline de Mello Gonçalves
    • 1
  • Ângela Zanatta
    • 1
  • Mateus Struecker da Rosa
    • 1
  • Samanta Oliveira Loureiro
    • 1
  • Carmen Regla Vargas
    • 3
    • 4
  • Guilhian Leipnitz
    • 1
    • 5
  • Diogo Onofre Gomes de Souza
    • 1
    • 5
  • Moacir Wajner
    • 1
    • 3
    • 5
  1. 1.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Departamento de Ciências BiológicasUniversidade Regional Integrada do Alto Uruguai e das MissõesErechimBrazil
  3. 3.Serviço de Genética MédicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  4. 4.Programa de Pós-Graduação em Ciências FarmacêuticasUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  5. 5.Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

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