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Effect of Glutamine Synthesis Inhibition with Methionine Sulfoximine on the Nitric Oxide–Cyclic GMP Pathway in the Rat Striatum Treated Acutely with Ammonia: A Microdialysis Study

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Abstract

Ammonia neurotoxicity is associated with overactivation of N-methyl-d-aspartate (NMDA) receptors leading to enhanced nitric oxide and cyclic GMP synthesis and to accumulation of reactive oxygen and nitrogen species. Ammonia is detoxified in the brain via synthesis of glutamine, which if accumulated in excess contributes to astrocytic swelling, mitochondrial dysfunction and cerebral edema. This study was aimed at testing the hypothesis that the activity of the NMDA/NO/cGMP pathway is controlled by the ammonia-induced production of Gln in the brain. Ammonium chloride (final concentration 5 mM), infused for 40 min to the rat striatum via a microdialysis probe, caused a significant increase in Gln (by 40%), NO oxidation products (nitrite+nitrate = NOx) (by 35%) and cGMP (by 50%) concentration in the microdialysate. A Gln synthetase inhibitor, methionine sulfoximine (MSO, 5 mM), added directly to the microdialysate, completely prevented ammonia-mediated production of Gln, and paradoxically, it increased ammonia-mediated production of NOx and cGMP by 230% and 250%, respectively. Of note, MSO given alone significantly reduced basal Gln concentration in the rat striatum, had no effect on the basal NOx concentration, and attenuated basal concentration of cGMP in the microdialysate by 50%. The results of the present study suggest that Gln, at physiological concentrations, may ameliorate excessive activation of the NO–cGMP pathway by neurotoxic concentrations of ammonia. However, in view of potential direct interference of MSO with the pathway, exogenously added Gln and less toxic modulators of Gln content and/or transport will have to be employed in further studies on the underlying mechanisms.

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Acknowledgments

The study was supported by Ministry of Science and Information, Grant 2P05A 066 28 (to J.A.), and by the competitive research funding of Pirkanmaa Hospital District (to S.S.O and P.S.).

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Authors and Affiliations

  1. Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, Warsaw, 02-106, Poland

    Wojciech Hilgier, Michal Węgrzynowicz & Jan Albrecht

  2. Medical Center of Postgraduate Education, Warsaw, Poland

    Michal Mączewski & Andrzej Beręsewicz

  3. The Centre for Laboratory Medicine and Department of Clinical Physiology and Nuclear Medicine, Tampere University Hospital, Tampere, Finland

    Simo S. Oja

  4. University of Tampere Medical School, Tampere, Finland

    Pirjo Saransaari

Authors
  1. Wojciech Hilgier
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  2. Michal Węgrzynowicz
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  3. Michal Mączewski
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  5. Simo S. Oja
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Corresponding author

Correspondence to Jan Albrecht.

Additional information

Special issue article in honor of Dr. Frode Fonnum.

Wojciech Hilgier and Michal Węgrzynowicz contributed equally to this work.

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Hilgier, W., Węgrzynowicz, M., Mączewski, M. et al. Effect of Glutamine Synthesis Inhibition with Methionine Sulfoximine on the Nitric Oxide–Cyclic GMP Pathway in the Rat Striatum Treated Acutely with Ammonia: A Microdialysis Study. Neurochem Res 33, 267–272 (2008). https://doi.org/10.1007/s11064-007-9455-1

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  • DOI: https://doi.org/10.1007/s11064-007-9455-1

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