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Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo
Author(s) -
Görg Boris,
Qvartskhava Natalia,
Keitel Verena,
Bidmon Hans J.,
Selbach Oliver,
Schliess Freimut,
Häussinger Dieter
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22345
Subject(s) - rna , biochemistry , biology , astrocyte , microbiology and biotechnology , chemistry , endocrinology , gene , central nervous system
Oxidative stress plays a major role in cerebral ammonia toxicity and the pathogenesis of hepatic encephalopathy (HE). As shown in this study, ammonia induces a rapid RNA oxidation in cultured rat astrocytes, vital mouse brain slices, and rat brain in vivo. Ammonia‐induced RNA oxidation in cultured astrocytes is reversible and sensitive to MK‐801, 1,2‐Bis(o‐aminophenoxy)ethane‐N,N,N′,N′‐tetraacetic acid, apocynin, epigallocatechin gallate, and polyphenon 60, suggesting the involvement of N −methyl− D ‐aspartic acid (NMDA) receptor activation, Ca 2+ , nicotinamide adenine dinucleotide phosphate, and reduced form (NADPH) oxidase‐dependent oxidative stress. Also, hypo‐osmolarity, tumor necrosis factor alpha (TNF‐α), and diazepam increase RNA oxidation in cultured astrocytes, suggesting that the action of different HE‐precipitating factors converges at the level of RNA oxidation. Among the oxidized RNA species, 18S‐rRNA and the messenger RNA (mRNA) coding for the glutamate/aspartate transporter (GLAST) were identified. Cerebral RNA oxidation in acutely ammonia‐loaded rats in vivo is reversible and predominates in neuronal soma and perivascular astrocyte processes. In neuronal dendrites, oxidized RNA colocalizes with the RNA‐binding splicing protein neurooncological ventral antigen (NOVA)‐2 within putative RNA transport granules, which are also found in close vicinity to postsynaptic spines. This indicates that oxidized RNA species may participate in postsynaptic protein synthesis, which is a biochemical substrate for learning and memory consolidation. Neuronal and astroglial RNA oxidation increases also in vital mouse brain slices treated with ammonia and TNF‐α, respectively. Conclusion: Cerebral RNA oxidation is identified as a not yet recognized consequence of acute ammonia intoxication. RNA oxidation may affect gene expression and local protein synthesis and thereby provide another link between reactive oxygen species (ROS)/reactive nitrogen oxide species (RNOS) production and ammonia toxicity. (H EPATOLOGY 2008.)