The proposed research focuses upon ammonia as a prime cause of the neurological complications arising from both acute and chronic liver desease. Our hypothesis is that failure of the diseased liver to remove ammonia from the circulation causes CNS abnormalities of neurotransmitter (acetylcholine, glutamate, GABA) function, energy metabolism, and intracellular transport of reduced equivalents from cytoplasm to mitochondrion via the malate-aspartate shuttle. It is further proposed that, with time, hyperammonemia leads to inhibition of protein turnover in brain, abnormalities of blood-brain barrier function, and the development of an increased cerebral """"""""sensitivity"""""""" to ammonia, hypoxia, and other superimposed metabolic stresses. Interference by ammonia with these vital neurochemical processes is believed to give rise to the typical neuropathological picture of chronic hepatic encephalopathy. To test these hypotheses, we have chosen a multifaceted approach: 1) To examine the cerebral uptake and metabolism of 13N-ammonia and 13N-amino acids in rats with portacaval shunts and in patients with liver disease; 2) To determine the effect of acute and chronic hyperammonemia, with and without superimposed hypoxia or ammonia loading, upon cerebral blood flow, oxidative energy coupling, carbohydrate metabolism, and acetylcholine turnover; 3) To clarify the role of alpha-ketoglutaramate and of other alpha-keto acids in relation to the symptoms of experimental hepatic coma; and 4) To assess the effects of chronic portal-systemic shunting and hyperammonemia on the rates of protein synthesis and degradation in brain and on the permeability of the blood-brain barrier to amino acids and other agents. It is anticipated that these investigations will clarify the mechanisms by which ammonia causes neurotoxicity and will suggest more effective methods to prevent this toxicity in patients with liver disease.
Dienel, Gerald A; Cruz, Nancy F (2016) Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats. Neurochem Res 41:16-32 |
Cooper, Arthur J L (2011) 13N as a tracer for studying glutamate metabolism. Neurochem Int 59:456-64 |