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Folic Acid Protects Against Glutamate-Induced Excitotoxicity in Hippocampal Slices Through a Mechanism that Implicates Inhibition of GSK-3β and iNOS

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Abstract

Folic acid (folate) is a vitamin of the B-complex group crucial for neurological function. Considering that excitotoxicity and cell death induced by glutamate are involved in many disorders, the potential protective effect of folic acid on glutamate-induced cell damage in rat hippocampal slices and the possible intracellular signaling pathway involved in such effect were investigated. The treatment of hippocampal slices with folic acid (100 μM) significantly abrogated glutamate (1 mM)-induced reduction of cell viability measured by MTT reduction assay and inhibited glutamate-induced D-[3H]-aspartate release. To investigate the putative intracellular signaling pathways implicated in the protective effect of folic acid, we used a PI3K inhibitor, LY294002, which abolished the protective effects of folic acid against glutamate-induced cell damage and D-[3H] aspartate release. Moreover, hippocampal slices incubated with folic acid alone for 30 min presented increased phosphorylation of GSK-3β at Ser9, indicating an inhibition of the activity of this enzyme. Furthermore, folic acid in the presence of glutamate insult in hippocampal slices maintained for an additional period of 6 h in fresh culture medium without glutamate and/or folic acid induced phosphorylation of GSK-3β and β-catenin expression. In addition, glutamate-treated hippocampal slices showed increased iNOS expression that was reversed by folic acid. In conclusion, the results of this study show that the protective effect of folic acid against glutamate-induced excitotoxicity may involve the modulation of PI3K/GSK-3β/β-catenin pathway and iNOS inhibition.

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Abbreviations

FA:

Folic acid

Glu:

Glutamate

GSK3β:

Glycogen synthase kinase 3β

LY 294002:

[2-(4-Morpholinyl)-8-phenyl-4H-1benzo-pyran-4-one

iNOS:

Inducible nitric oxide synthase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NO:

Nitric oxide

PI3K:

phosphoinisitide-3 kinase

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Acknowledgements

Research supported by grants from the Brazilian funding agencies: Conselho de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), CAPES/DGU Project No. 173/2008; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); IBN-Net/CNPq; NENASC project (PRONEX program CNPq/FAPESC). C.I. Tasca and A.L.S. Rodrigues are recipients of CNPq productivity fellowship. This work was also supported by grants from the Spanish Ministry of Science and Innovation SAF2009-12150, Ministry of Education PBH2007-0004-PC, and the Spanish Ministry of Health (Instituto de Salud Carlos III) RETICS-RD06/0026.

Author Contribution

JB, SM, JE, MGL, CIT, and ASR were involved in experimental design. JB, SM, TDC, MDMS, and JE were responsible for performing the work. JB, TDC, MDMS, ALSR, MGL, and CIT wrote the manuscript. All authors approved this version of the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil

    Josiane Budni, Tharine Dal-Cim, Carla Ines Tasca & Ana Lúcia Severo Rodrigues

  2. Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Josiane Budni

  3. Laboratório de Doenças Neurodegenerativas, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Josiane Budni

  4. Neuroscience Laboratory and Neurodegenerative Disease Laboratory, Graduate Program in Health Sciences, Academic Unit of Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, 8806-000, Brazil

    Josiane Budni

  5. Universidade do Contestado, Pharmacy School, Canoinhas, SC, 89460-000, Brazil

    Simone Molz

  6. Department of Pharmacology and Therapeutics, Universidad Autónoma de Madrid, 28050, Madrid, Spain

    Maria Dolores Martín-de-Saavedra, Javier Egea & Manuela G. Lopéz

  7. Instituto Teófilo Hernando, Universidad Autonoma de Madrid, Madrid, Spain

    Maria Dolores Martín-de-Saavedra, Javier Egea & Manuela G. Lopéz

  8. HIV Unit. Hospital La Paz/Autónoma University School of Medicine. IdiPAZ. Universidad Autonoma de Madrid, Departamento de Farmacologia, Madrid, Spain

    Javier Egea & Manuela G. Lopéz

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  1. Josiane Budni
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  2. Simone Molz
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  3. Tharine Dal-Cim
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  6. Manuela G. Lopéz
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  7. Carla Ines Tasca
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  8. Ana Lúcia Severo Rodrigues
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Correspondence to Josiane Budni.

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Budni, J., Molz, S., Dal-Cim, T. et al. Folic Acid Protects Against Glutamate-Induced Excitotoxicity in Hippocampal Slices Through a Mechanism that Implicates Inhibition of GSK-3β and iNOS. Mol Neurobiol 55, 1580–1589 (2018). https://doi.org/10.1007/s12035-017-0425-6

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