Inflammation and hepatic encephalopathy: Ibuprofen restores learning ability in rats with portacaval shunts

One of the neurological alterations in patients with minimal or overt hepatic encephalopathy is cognitive impairment. This impairment is reproduced in rats with chronic liver failure due to portacaval shunt (PCS). These rats show decreased ability to learn a conditional discrimination task in a Y-maze, likely due to reduced function of the glutamate-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in brain. It has been proposed that inflammation exacerbates the neuropsychological alterations induced by hyperammonemia, suggesting that inflammation-associated alterations may contribute to cognitive impairment in hepatic encephalopathy. This study assessed whether treatment with an anti-inflammatory drug, ibuprofen, is able to restore the function of the glutamate-NO-cGMP pathway in cerebral cortex in brain in vivo and/or learning ability in PCS rats. We show that PCS rats have increased levels of interleukin-6 and increased activities of cyclooxygenase and of inducible NO synthase in cerebral cortex, indicating the presence of inflammation. Chronic treatment with ibuprofen normalizes cyclooxygenase and inducible NO synthase activities but not interleukin-6 levels. Moreover, ibuprofen normalizes the function of the glutamate-NO-cGMP pathway in cerebral cortex in vivo and completely restores the ability of rats with chronic liver failure to learn the Y-maze task. This supports that inflammation contributes to the cognitive impairment in hepatic encephalopathy. Conclusion: the results reported point to the possible therapeutic utility of decreasing inflammation in the treatment of the cognitive deficits in patients with minimal or overt hepatic encephalopathy.