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

• Published in: Toxicological sciences Vol. 117; no. 1; pp. 163 - 168
• Main Authors: Hilgier, Wojciech, Węgrzynowicz, Michał, Ruszkiewicz, Joanna, Oja, Simo S., Saransaari, Pirjo, Albrecht, Jan
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2010
• Subjects: Ammonia - blood; Ammonia - toxicity; Animals; astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Cell Line, Tumor; Extracellular Space - metabolism; glutathione; Glutathione - metabolism; hepatic encephalopathy; hyperammonemia; Hyperammonemia - metabolism; Male; microdialysis; prefrontal cortex; Prefrontal Cortex - drug effects; Rats; Rats, Sprague-Dawley; γ-glutamyl-transpeptidase
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfq171

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.