Ammonia and enzymes of ammonia metabolism in different brain regions in hyperammonemia

Abstract

Hyperammonemia plays a central role in the pathogenesis of hepatic encephalopathy but the mechanisms that lead to such a dysfunction of the brain are not yet fully understood. It is also unknown how enzymes of ammonia and glutamate metabolism in different brain areas respond to an excess of ammonia. We investigated the effect of ammonia on the catalytic activities of key enzymes of ammonia and glutamate metabolism in mitochondria and cytoplasm of the neocortex, cerebellum, hippocampus, striatum, and liver. We found that acute hyperammonemia caused by administration of a lethal dose of ammonium acetate to rats led to an increase in the ammonia content in all tissues, which correlated with the initial endogenous ammonia content in these tissues. The activities of all analyzed enzymes, glutamine synthetase, glutaminase, glutamate dehydrogenase, adenosine deaminase, AMP-deaminase, aspartate aminotransferase, and alanine aminotransferase, was unevenly distributed in four brain areas and the liver and changed differently in acute ammonia intoxication. The results suggest that enzymes of glutamate and ammonia metabolism are functionally different in different tissues, while the mechanisms of the regulation of these enzymes are fundamentally different in the liver, neocortex, cerebellum, striatum, and hippocampus. These data make a new contribution to our understanding of the pathogenesis of hepatic encephalopathy and other forms of hyperammonemia.