Impaired enzymatic antioxidant defense in erythrocytes of rats with ammonia-induced encephalopathy: role NMDA receptors

Abstract

Hepatic encephalopathy (HE), a medical term that deals with a neuropsychiatric disorder seen in patients with severe hepatic dysfunction, has been known for more than a century, however, pathogenetic mechanisms underlying cerebral dysfunction during conditions of liver disease are still not entirely understood. There is a consensus that an accumulation of ammonia in brain as a result of impaired detoxification capacity of the liver or the appearance of a portosystemic shunt is a primary cause of HE. Current evidence suggests that ammonia toxicity is mediated by hyperactivation of glutamate receptors, mainly N-methyl-D-aspartate receptors (NMDA-R) and affects many processes of aerobic metabolism that provides energy for a myriad of specific functions and viability of nerve cells. Recent reports on the presence of functional NMDA receptors in erythrocytes and deviations from normal ranges in many blood test parameters that was indicative of impaired hemodynamics and reduced carrying capacity for oxygen in erythrocytes in most patients with HE implicate the relationship between “erythrocyte damage” and cerebral dysfunction. In order to understand how, during hyperammonemia, disturbances in energy metabolism in brain that needs a constant supply of a high level of oxygen in the blood lead to encephalopathy, it is necessary to reveal ammonia-induced disorders in energy metabolism and antioxidant defense system of erythrocytes and explore the potential role of ammonia in reduced brain oxygenation. To detect the said missing link, the activities of erythrocyte antioxidant enzymes and concentrations of GSH, GSSG and H2O2 were measured in animals with hyperammonemia by using MK-801, a powerful noncompetitive NMDA receptor antagonist. It was found that the accumulation of ammonia in the blood of animals with hyperammonemia occurs within rat erythrocytes in large amounts and makes these cells which do not contain enzymes for the removal of ammonia, more susceptible to a prooxidant environment of ammonia created during oxidative stress that was completely or partially inhibited with the help of MK-801. Data obtained provide a support to identification of extra risk factors in cognitive disorders and in the prediction of unfavorable outcome with hypoperfusion in patients with elevated concentrations of ammonia in the blood.