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Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation

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Abstract

Diabetes is a metabolic disease characterized by high fasting-glucose levels. Diabetic complications have been associated with hyperglycemia and high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation endproducts (AGEs) formation derived from glucose. Diabetic patients have a higher risk of developing neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease. Herein, we examined the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in acute hippocampal slices, and investigated some of the mechanisms that could mediate these effects. Glucose, MG and CEL did not alter reactive oxygen species (ROS) formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions, examined by aminoguanidine and l-lysine co-incubation, did not mediate these changes. Acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices, suggesting that conditions of high glucose concentrations are primarily toxic by elevating the rates of these glycation compounds, such as MG, and by generation of protein cross-links. Alterations in the secretion of S100B and the glutamatergic activity mediated by MG and AGEs can contribute to the brain dysfunction observed in diabetic patients.

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Acknowledgments

This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Financiadora de Estudos e Projetos (FINEP)—Instituto Brasileiro de Neurociências (IBN Net) 01.06.0842-00, Federal University of Rio Grande do Sul (UFRGS) and Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (INCTEN/CNPq).

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Authors and Affiliations

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

    Fernanda Hansen, Cíntia Eickhoff Battú, Fabiana Galland, Franciane Lirio, Patrícia Nardin & Carlos-Alberto Gonçalves

  2. Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Trindade, Florianópolis, SC, 88040-970, Brazil

    Márcio Ferreira Dutra

  3. Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 90046-900, Brazil

    Núbia Broetto

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  1. Fernanda Hansen
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  2. Cíntia Eickhoff Battú
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  3. Márcio Ferreira Dutra
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  4. Fabiana Galland
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  5. Franciane Lirio
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  7. Patrícia Nardin
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  8. Carlos-Alberto Gonçalves
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Correspondence to Carlos-Alberto Gonçalves.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, and all procedures performed in this study were in accordance with the ethical standards of the institution at which the studies were conducted (Institutional Animal Care and Use Committee (IACUC), approval number 28035).

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Hansen, F., Battú, C.E., Dutra, M.F. et al. Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation. Amino Acids 48, 375–385 (2016). https://doi.org/10.1007/s00726-015-2091-1

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