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Detoxification of Ammonia in Mouse Cortical GABAergic Cell Cultures Increases Neuronal Oxidative Metabolism and Reveals an Emerging Role for Release of Glucose-Derived Alanine

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Abstract

Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme. Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways in a mouse neuronal–astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure enhanced the synthesis and release of alanine. Collectively, our results demonstrate that (1) formation of glutamine is seminal for detoxification of ammonia; (2) neuronal oxidative metabolism is increased in the presence of ammonia; and (3) synthesis and release of alanine is likely to be important for ammonia detoxification as a supplement to formation of glutamine.

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Abbreviations

GDH:

Glutamate dehydrogenase

GS:

Glutamine synthetase

GSH:

Glutathione

HE:

Hepatic encephalopathy

LC–MS:

Liquid chromatography–mass spectrometry

MCL:

Molecular carbon labeling

NMRS:

Nuclear magnetic resonance spectroscopy

PC:

Pyruvate carboxylase

PDH:

Pyruvate dehydrogenase

TCA:

Tricarboxylic acid

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Acknowledgments

The skilful technical assistance of Ms Ann Lene Vigh is highly appreciated. A travel grant to Renata Leke from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Capes is cordially acknowledged. The experimental study has been supported by grants from the Danish Medical Research Council (271-08-0505; 271-07-0267). The Carlsberg Foundation is cordially thanked for supporting a post doc. fellowship to Lasse Bak (2007–2010).

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Authors and Affiliations

  1. Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

    Renata Leke & Luis V. Portela

  2. Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark

    Renata Leke, Lasse K. Bak, Malene Anker, Arne Schousboe & Helle S. Waagepetersen

  3. Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    Torun M. Melø & Ursula Sonnewald

  4. PET Centre, Aarhus University Hospital, 8000, Aarhus, Denmark

    Michael Sørensen & Susanne Keiding

  5. Department of Medicine V, Aarhus University Hospital, 8000, Aarhus, Denmark

    Michael Sørensen, Susanne Keiding, Hendrik Vilstrup & Peter Ott

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  1. Renata Leke
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  2. Lasse K. Bak
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  3. Malene Anker
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Correspondence to Lasse K. Bak.

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Leke, R., Bak, L.K., Anker, M. et al. Detoxification of Ammonia in Mouse Cortical GABAergic Cell Cultures Increases Neuronal Oxidative Metabolism and Reveals an Emerging Role for Release of Glucose-Derived Alanine. Neurotox Res 19, 496–510 (2011). https://doi.org/10.1007/s12640-010-9198-7

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