Original Paper

Metabolic Brain Disease

, Volume 24, Issue 1, pp 119-134

First online:

RNA oxidation and zinc in hepatic encephalopathy and hyperammonemia

  • Freimut SchliessAffiliated withHeinrich-Heine-Universität Düsseldorf, Klinik für Gastroenterologie, Hepatologie, und InfektiologieProfil Institut für Stoffwechselforschung GmbH
  • , Boris GörgAffiliated withHeinrich-Heine-Universität Düsseldorf, Klinik für Gastroenterologie, Hepatologie, und Infektiologie
  • , Dieter HäussingerAffiliated withHeinrich-Heine-Universität Düsseldorf, Klinik für Gastroenterologie, Hepatologie, und Infektiologie Email author 

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Hepatic encephalopathy is a neuropsychiatric manifestation of acute and chronic liver failure. Ammonia plays a key role in the pathogenesis of hepatic encephalopathy by inducing astrocyte swelling and/or sensitizing astrocytes to swelling by a heterogeneous panel of precipitating factors and conditions. Whereas astrocyte swelling in acute liver failure contributes to a clinically overt brain edema, a low grade glial edema without clinically overt brain edema is observed in hepatic encephalopathy in liver cirrhosis. Astrocyte swelling produces reactive oxygen and nitrogen oxide species (ROS/RNOS), which again increase astrocyte swelling, thereby creating a self-amplifying signaling loop. Astroglial swelling and ROS/RNOS increase protein tyrosine nitration and may account for neurotoxic effects of ammonia and other precipitants of hepatic encephalopathy. Recently, RNA oxidation and an increase of free intracellular zinc ([Zn2+]i) were identified as further consequences of astrocyte swelling and ROS/RNOS production. An elevation of [Zn2+]i mediates mRNA expression of metallothionein and the peripheral benzodiazepine receptor (PBR) induced by hypoosmotic astrocyte swelling. Further, Zn2+ mediates RNA oxidation in ammonia-treated astrocytes. In the brain of hyperammonemic rats oxidized RNA localizes in part to perivascular astrocyte processes and to postsynaptic dendritic spines. RNA oxidation may impair postsynaptic protein synthesis, which is critically involved in learning and memory consolidation. RNA oxidation offers a novel explanation for multiple disturbances of neurotransmitter systems and gene expression and the cognitive deficits observed in hepatic encephalopathy.


Astrocytes Cell volume Oxidative stress Ammonia Brain Peripheral benzodiazepine receptor Metallothionein