European Journal of Molecular & Clinical Medicine

Abstract

Chronic liver disease (e.g. cirrhosis) affects brain function. There is a high incidence of mild cognitive impairment and psychomotor slowing in patients with cirrhosis. This condition, known as minimal hepatic encephalopathy (MHE) affects more than 2 million people in the European Union and has serious health, social and economic consequences. There are no effective treatments for MHE. Rat models of MHE reproduce cognitive and motor alterations seen in patients, showing reduced performance in different types of cognitive tests, including learning a conditional discrimination task in a Y maze. We have shown that reduced ability to learn the Y maze task is due to reduced function of the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum, assessed in vivo by microdialysis. This results in reduced formation of cGMP in response to activation of NMDA receptors and impairment of learning ability. We have found that both hyperammonemia and neuroinflammation contribute to impair this pathway. The effect is mediated by enhanced tonic activation of NMDA and GABAA receptors and of MAP-kinase p38. Based on this mechanistic studies, we have designed and tested new therapeutic strategies acting on specific targets in the brain, which have successfully restored the function of the glutamate-NO-cGMP pathway in vivo and learning ability in rats with