Neurotoxicity Research

, Volume 33, Issue 3, pp 593–606 | Cite as

Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice

  • Alexandre Umpierrez Amaral
  • Bianca Seminotti
  • Janaína Camacho da Silva
  • Francine Hehn de Oliveira
  • Rafael Teixeira Ribeiro
  • Carmen Regla Vargas
  • Guilhian Leipnitz
  • Abel Santamaría
  • Diogo Onofre Souza
  • Moacir Wajner


Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH) activity. Patients usually present progressive cortical leukodystrophy and commonly develop acute bilateral striatal degeneration mainly during infections that markedly worse their prognosis. A role for quinolinic acid (QA), a key metabolite of the kynurenine pathway, which is activated during inflammatory processes, on the pathogenesis of the acute striatum degeneration occurring in GA I was proposed but so far has not yet been evaluated. Therefore, we investigated whether an acute intrastriatal administration of quinolinic acid (QA) could induce histopathological alterations in the striatum of 30-day-old wild-type (WT) and GCDH knockout (Gcdh−/−) mice. Striatum morphology was evaluated by hematoxylin and eosin, T lymphocyte presence (CD3), and glial activation (GFAP and S100β) by immunohistochemistry and 3-nitrotyrosine (YNO2) by immunofluorescence. QA provoked extensive vacuolation, edema, and especially lymphocyte infiltration in the striatum of Gcdh−/−. QA also enhanced CD3 staining and the number of YNO2 positive cells in Gcdh−/− mice, relatively to WT, indicating T lymphocyte infiltration and nitrosative stress, respectively. QA-treated WT mice also showed an increase of GFAP and S100β staining, which is indicative of reactive astrogliosis, whereas the levels of these astrocytic proteins were not changed in Gcdh−/− QA-injected mice. The present data indicate that QA significantly contributes to the histopathological changes observed in the striatum of Gcdh−/− mice.


Glutaric acidemia type I Acute striatum degeneration Neuroinflammation Quinolinic acid Histopathology Nitrosative stress 


Funding Information

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, Hospital de Clínicas de Porto Alegre #140544, Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul #PIBICAF 29490, Financiadora de Estudos e Projetos # 01.06.0842-00, and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN, # 573677/2008-5).

Compliance with Ethical Standards

This study was performed in strict accordance with the Principles of Laboratory Animal Care, National Institute of Health of United States of America, NIH, publication no. 85-23, revised in 2011, the International Guiding Principles for Biomedical Research Involving Animals, and approved by the Ethical Committee for the Care and Use of Laboratory Animals of the Hospital de Clínicas de Porto Alegre (no. 140544).

Conflicts of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Alexandre Umpierrez Amaral
    • 1
    • 2
  • Bianca Seminotti
    • 1
  • Janaína Camacho da Silva
    • 1
  • Francine Hehn de Oliveira
    • 3
  • Rafael Teixeira Ribeiro
    • 1
  • Carmen Regla Vargas
    • 1
    • 4
    • 5
  • Guilhian Leipnitz
    • 1
    • 6
  • Abel Santamaría
    • 7
  • Diogo Onofre Souza
    • 1
    • 6
  • Moacir Wajner
    • 1
    • 4
    • 6
  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 PatologiaHospital de Clinicas de Porto AlegrePorto AlegreBrazil
  4. 4.Serviço de Genética MédicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  5. 5.Programa de Pós-Graduação em Ciências FarmacêuticasUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  6. 6.Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  7. 7.Laboratorio de Aminoácidos ExcitadoresInstituto Nacional de Neurología y NeurocirugíaMéxicoMexico

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