ABSTRACT
Background Defective learning/memory ability is a feature of MHE. However, the exact pathophysiological mechanisms leading to the impairment of learning/memory ability in MHE remain not clearly understood. Methods MHE rat modeling by intraperitoneal injection of TAA was successfully established using a Morris water maze, BAEP, and EEG tests. COMT inhibitor, a protein involved in the accumulation of dopamine (DA), was found to be up-regulated in cirrhotic livers in MHE by 2-DE/MS. Results The levels of DA in cirrhotic livers, serums and hippocampuses in the MHE group were more significantly increased than in the control group. In the hippocampuses of MHE rats, NMDA-induced formation of cGMP was reduced by 40 % as determined by in vivo brain microdialysis. Activation of sGC by NO was reduced by 38 %. The expression of NMDAR1, CaM, nNOS and sGC in the hippocampus in the MHE group were more significantly decreased than in controls. Chronic exposure of cultured hippocampus neurons to DA (50 µM) reduced by 53 % the NMDA-induced formation of cGMP. Activation of sGC by NO in these neurons was reduced by 44 %. Down-regulated NMDAR1, CaM, nNOS and sGC were also detected in neurons treated with dopamine, in contrast with the controls. Conclusions This study suggests that when the glutamate-NO-cGMP pathway in the hippocampus is inhibited by the elevation of DA from cirrhotic livers, this in turn may lead to the impairment of learning and memory ability of MHE.
