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Molecular Neurobiology

, Volume 56, Issue 7, pp 4945–4959 | Cite as

Involvement of the Cholinergic Parameters and Glial Cells in Learning Delay Induced by Glutaric Acid: Protection by N-Acetylcysteine

  • Fernanda Silva Rodrigues
  • Viviane Nogueira de Zorzi
  • Marla Parizzi Funghetto
  • Fernanda Haupental
  • Alexandra Seide Cardoso
  • Sara Marchesan
  • Andréia M. Cardoso
  • Maria Rosa C. Schinger
  • Alencar Kolinski Machado
  • Ivana Beatrice Mânica da Cruz
  • Marta Maria Medeiros Frescura Duarte
  • Léder L. Xavier
  • Ana Flavia Furian
  • Mauro Schneider Oliveira
  • Adair Roberto Soares Santos
  • Luiz Fernando Freire Royes
  • Michele Rechia FigheraEmail author
Article

Abstract

Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 μmol g body weight−1, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.

Keywords

Glutaric acid Striatum N-acetylcysteine Procedural learning Memory Acetylcholinesterase activity α7nAChR Inflammation 

Notes

Funding Information

This work was supported by the CNPq (grants: Pronem 11/2082-4). M.R. Fighera, L.F.F. Royes, A.F. Furian, M. Schneider-Oliveira, and A.R.S. Santos are recipients of CNPq fellowships.

Compliance with Ethical Standards

Laboratory experiments were performed in accordance with national and international legislations (Brazilian College of Animal Experimentation (COBEA) and the US Public Health Service’s Policy on Humane Care and Use of Laboratory Animals-PHS Policy) and approved by the Ethics Committee for Animal Research of Universidade Federal de Santa Maria (UFSM; Permit Number: 116/2010) and Universidade Federal de Santa Catarina (UFSC; Permit Number: 5386180317).

Conflict of interest

All authors confirm that there is no competing financial conflict of interest.

Supplementary material

12035_2018_1395_MOESM1_ESM.docx (350 kb)
ESM 1 (DOCX 349 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Fernanda Silva Rodrigues
    • 1
    • 2
    • 3
    • 4
  • Viviane Nogueira de Zorzi
    • 1
    • 2
  • Marla Parizzi Funghetto
    • 1
    • 2
  • Fernanda Haupental
    • 1
    • 2
  • Alexandra Seide Cardoso
    • 1
    • 2
  • Sara Marchesan
    • 5
  • Andréia M. Cardoso
    • 5
  • Maria Rosa C. Schinger
    • 5
  • Alencar Kolinski Machado
    • 6
  • Ivana Beatrice Mânica da Cruz
    • 6
  • Marta Maria Medeiros Frescura Duarte
    • 6
  • Léder L. Xavier
    • 7
  • Ana Flavia Furian
    • 6
  • Mauro Schneider Oliveira
    • 6
  • Adair Roberto Soares Santos
    • 3
    • 4
  • Luiz Fernando Freire Royes
    • 2
    • 4
    • 5
    • 6
  • Michele Rechia Fighera
    • 1
    • 2
    • 4
    • 5
    • 6
    Email author
  1. 1.Centro de Ciências da Saúde, Departamento de Neuropsiquiatria, Laboratório de Neuropsiquiatria Experimental e ClínicoUniversidade Federal de Santa MariaSanta MariaBrazil
  2. 2.Centro de Educação Física e Desportos, Departamento de Métodos e Técnicas Desportivas, Laboratório de Bioquímica do Exercício (BIOEX)Universidade Federal de Santa MariaSanta MariaBrazil
  3. 3.Centro de Ciências Biológicas, Laboratório de Neurobiologia da Dor e InflamaçãoUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  4. 4.Centro de Ciências Biológicas, Programa de Pós-Graduação em NeurociênciasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  5. 5.Centro de Ciências Naturais e Exatas, Programa de Pós-graduação em Ciências Biológicas: Bioquímica ToxicológicaUniversidade Federal de Santa MariaSanta MariaBrazil
  6. 6.Centro de Ciências da Saúde Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e FarmacologiaUniversidade Federal de Santa MariaSanta MariaBrazil
  7. 7.Faculdade de Biociências, Laboratório Central de Microscopia e Microanálise, Departamento de Ciências FisiológicaPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil

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