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A neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitability

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Abstract

Hyperammonemia is a common finding in children with methylmalonic acidemia. However, its contribution to methylmalonate-induced excitotoxicty is poorly understood. The aim of this study was to evaluate the mechanisms by which ammonia influences in the neurotoxicity induced by methylmalonate (MMA) in mice. The effects of ammonium chloride (NH4Cl 3, 6, and 12 mmol/kg; s.c.) on electroencephalographic (EEG) and behavioral convulsions induced by MMA (0.3, 0.66, and 1 µmol/2 µL, i.c.v.) were observed in mice. After, ammonia, TNF-α, IL1β, IL-6, nitrite/nitrate (NOx) levels, mitochondrial potential (ΔΨ), reactive oxygen species (ROS) generation, Methyl-Tetrazolium (MTT) reduction, succinate dehydrogenase (SDH), and Na+, K+-ATPase activity levels were measured in the cerebral cortex. The binding of [3H]flunitrazepam, release of glutamate-GABA; glutamate decarboxylase (GAD) and glutamine synthetase (GS) activity and neuronal damage [opening of blood brain barrier (BBB) permeability and cellular death volume] were also measured. EEG recordings showed that an intermediate dose of NH4Cl (6 mmol/kg) increased the duration of convulsive episodes induced by MMA (0.66 μmol/2 μL i.c.v). NH4Cl (6 mmol/kg) administration also induced neuronal ammonia and NOx increase, as well as mitochondrial ROS generation throughout oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) to DCF-RS, followed by GS and GAD inhibition. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na+, K+-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [3H]flunitrazepam binding, and GABA release after MMA injection. On the basis of our findings, the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate (GABA) cycle and contribute to MMA-induced excitability.

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Acknowledgments

This work was supported by the CNPq (grants: Pronem: 11/2082-4). M.R. Fighera, L.F.F. Royes Furian A.F.; Schneider-Oliveira M are recipients of CNPq fellowships. The authors thank Gustavo Cassol for revision of references. All authors confirm that there is no competing financial conflict of interest.

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Authors and Affiliations

  1. Laboratório de Bioquímica do Exercício (BioEx), Programa de Pós-Graduação em Educação Física, Centro de Educação Física e Desportos, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Luiz Fernando Freire Royes, Leandro Rodrigo Ribeiro, Iuri Domingues Della-Pace, Fernanda Silva Rodrigues, Ana Paula de Oliveira Ferreira, Mauro Eduardo Porto da Silveira Junior & Luís Roberto Hart da Silva

  2. Programa de Pós-graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Patrícia Gabbi, Ana Flavia Furian & Mauro Schneider Oliveira

  3. Departamento de Neuropsiquiatria, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Michele Rechia Fighera

  4. Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Fernando Dobrachinski, Félix Alexandre Antunes Soares & Sara Marchesan

  5. Laboratorio de Neuroendocrinologia, Instituto de Biociência, Universidade Federal do Pará-UFPA, Castanhal, Brazil

    Alan Barroso Araújo Grisólia, Danielle Valente Braga & Anderson Manoel Herculano Oliveira da Silva

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  1. Luiz Fernando Freire Royes
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  2. Patrícia Gabbi
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Royes, L.F.F., Gabbi, P., Ribeiro, L.R. et al. A neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitability. Amino Acids 48, 1373–1389 (2016). https://doi.org/10.1007/s00726-015-2164-1

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