Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy.
Cell culture studies and animal models point to an important role of oxidative/nitrosative stress in the pathogenesis of cerebral ammonia toxicity. However, it is unknown whether oxidative/nitrosative stress in the brain is also characteristic of hepatic encephalopathy (HE) in humans. We therefore analyzed post mortem cortical brain tissue samples from patients with cirrhosis dying with or without HE in comparison with brains from patients without liver disease. Significantly elevated levels of protein tyrosine-nitrated proteins, heat shock protein-27, and 8-hydroxyguanosine as a marker for RNA oxidation were found in the cerebral cortex of HE patients, but not of patients with cirrhosis but without HE. Glutamine synthetase (GS) activity was significantly decreased, whereas GS protein expression was not significantly affected. Protein expression of the glutamate/aspartate cotransporter was up-regulated in HE, whereas protein expression of neuronal and inducible nitric oxide synthases, manganese-dependent and copper/zinc-dependent superoxide dismutase, and glial glutamate transporter-1 were not significantly increased.


CONCLUSIONS
These data indicate that HE in patients with cirrhosis is associated with oxidative/nitrosative stress, protein tyrosine nitration, and RNA oxidation, suggesting a role of oxidative stress in the pathogenesis of HE in patients with cirrhosis.
Görg
Boris
B
Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich-Heine-University, Düsseldorf, Germany.
Qvartskhava
Natalia
N
Bidmon
Hans-Jürgen
HJ
Palomero-Gallagher
Nicola
N
Kircheis
Gerald
G
Zilles
Karl
K
Häussinger
Dieter
D
D000328:Adult; D000368:Aged; D027322:Amino Acid Transport System X-AG / Q000032:analysis / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000032:analysis / Q000378:metabolism; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000032:analysis / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000032:analysis / Q000378:metabolism*; D018384:Oxidative Stress; D012313:RNA / Q000032:analysis / Q000378:metabolism; D014443:Tyrosine / Q000032:analysis / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D015415:Biomarkers; D027342:Excitatory Amino Acid Transporter 2; D055551:HSP27 Heat-Shock Proteins; D009566:Nitrates; D006151:Guanosine; C046215:8-hydroxyguanosine; D014443:Tyrosine; D012313:RNA; D005974:Glutamate-Ammonia Ligase