Direct exposure to ammonia and hyperammonemia increase the extracellular accumulation and degradation of astroglia-derived glutathione in the rat prefrontal cortex.
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 gamma-glutamyltranspeptidase (gammaGT) 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 gammaGT activity. GSH remained increased during the whole 72-h incubation with 5 or 10mM ammonia in C6 glioma cells, where gammaGT 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.
Hilgier
Wojciech
W
Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Wegrzynowicz
Michal
M
Ruszkiewicz
Joanna
J
Oja
Simo S
SS
Saransaari
Pirjo
P
Albrecht
Jan
J
D000641:Ammonia / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D005110:Extracellular Space / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D022124:Hyperammonemia / Q000378:metabolism*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000641:Ammonia; D005978:Glutathione