Background: Ammonia is central in the pathogenesis of hepatic encephalopathy however it is believed systemic oxidative/nitrosative stress may play an important role in exacerbating the neuropsychological effects of hyperammonemia observed in patients with cirrhosis. Furthermore, it has recently been demonstrated in vitro that pathophysiological concentrations of ammonia induce oxidative/nitrosative stress in brain (cultured astrocytes), however this remains to be evaluated in vivo. The present study aims to investigate the role of oxidative/nitrosative stress in a well characterized hyperammonemic rat model of portacaval anastomosis (PCA). Methods: Rats were sacrificed 4 weeks following PCA or SHAM-operation. Ammonia, nitrate/nitrite, reactive oxygen species and total glutathione were measured in both plasma (arterial) and cerebrospinal fluid. Activities of antioxidant enzymes (catalase, superoxide dismutase and glutathione reductase/peroxidase) were measured in both plasma (arterial) and frontal cortex of the brain. Results: Ammonia concentrations were increased in both plasma (PCA: 173.7 ± 13.58uM vs SHAM: 77.8 ± 11.2uM; p<0.001) and cerebrospinal fluid (PCA: 146.6 ± 26.0uM vs SHAM: 31.5 ± 6.9uM; p<0.001) in PCA rats compared to SHAM operated controls. Furthermore, PCA rats showed a significant increase in catalase (PCA: 3.27 ± 0.03U/ml vs SHAM: 3.10 ± 0.05U/ml; p<0.05) and superoxide dismutase (PCA: 97.30 ± 0.47 vs SHAM: 95.57 ± 0.45 % inhibition; p<0.05) activities, but no significant differences were found in frontal cortex between the two groups. In addition, no significant changes in reactive oxygen species, nitrate/nitrite and total glutathione levels, nor in glutathione reductase and peroxidase activities were found in both plasma and brain tissue of PCA and SHAM rats. Conclusion: Rats with PCA develop hyperammonemia which leads to toxic levels of ammonia in the brain. This in turn does not induce oxidative/nitrosative stress systemically or centrally. Maintenance of systemic antioxidant activity in rats with PCA preserves a balanced redox status and prevents progression of encephalopathy.
