Journal Article

Direct Exposure to Ammonia and Hyperammonemia Increase the Extracellular Accumulation and Degradation of Astroglia-Derived Glutathione in the Rat Prefrontal Cortex

Wojciech Hilgier, Michał Węgrzynowicz, Joanna Ruszkiewicz, Simo S. Oja, Pirjo Saransaari and Jan Albrecht

in Toxicological Sciences

Volume 117, issue 1, pages 163-168
Published in print September 2010 | ISSN: 1096-6080
Published online June 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq171
Direct Exposure to Ammonia and Hyperammonemia Increase the Extracellular Accumulation and Degradation of Astroglia-Derived Glutathione in the Rat Prefrontal Cortex

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We endeavored here to shed light on the supply of glutathione (GSH) precursors from glial cells to neurons and on the interference of ammonia with this process. Administration of ammonium chloride (ammonia) via a microdialysis probe to the rat prefrontal cortex rapidly increased GSH content in the microdialysates. The increase was abrogated by the inhibitor of astrocytic energy metabolism fluoroacetate and the inhibitor of glutathione synthesis buthionine sulfoximine. GSH in the microdialysates was significantly elevated in rats with simple hyperammonemia (HA) or hepatic encephalopathy (HE) (three ip administrations of ammonium acetate or thioacetamide, respectively, at 24-h intervals), only when microdialysis was carried out in the presence of a γ-glutamyltranspeptidase (γGT) inhibitor acivicin. Extracellular GSH increased in cultured rat cortical astrocytes treated with 5mM ammonia for 1 h, but not for 3–72 h, which was the period of increased γGT activity. GSH remained increased during the whole 72-h incubation with 5 or 10mM ammonia in C6 glioma cells, where γGT activity is intrinsically low and was not increased by ammonia. Collectively, the results suggest that in rats with HA or HE ammonia specifically promote GSH synthesis and export from astrocytes and increase its extracellular degradation, which may improve the availability of precursors for GSH synthesis in neurons and their resistance to ammonia toxicity.

Keywords: hyperammonemia; hepatic encephalopathy; glutathione; γ-glutamyl-transpeptidase, microdialysis, prefrontal cortex; astrocytes

Journal Article.  3754 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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