Ammonia is a major toxin in the CNS and interferes with cerebral energy metabolism. Ammonia may exert its deleterious effect by interfering with the transport of """"""""reducing equivalents"""""""" between cytosol and mitochondria. With the use of a new inhibitor of aspartate aminotransferase, i.e. Beta-methyleneaspartate (BetaMA), we have shown that the malate-aspartate shuttle (MAS) operates in brain for the transport of reducing equivalents. The data strongly suggest that the MAS and tricarboxylic acid cycle are tightly linked. We wish to extend these studies to determine whether excess ammonia produces the same biochemical effects (e.g. decreased 02 consumption and decreased ATP) as does BetaMA, and to determine whether the effects are additive. The astrocytes in the brains of liver disease patients and in the brains of portacaval-shunted rats are morphologically abnormal (Alzheimer type II changes). This abnormality may be due to a greater susceptibility to ammonia-induced metabolic impairment in astrocytes than in neurons. To test this hypothesis, we will investigate the biochemical effects on cultures of neurons and astrocytes of acute and chronic exposure to excess ammonia and BetaMA. We will also use [13N]ammonia (13N, positron-emitter; t1/2=9.96 min) to determine to what extent normal metabolic compartmentation is disrupted in the hyperammonemic rat brain. The metabolism of 13N-labeled amino acids will be investigated in the brains of normal and hyperammonemic rats. Evidence will be sought that branched-chain amino acid mixtures exert their beneficial effects by acting to replenish small compartment (astrocytic) glutamate, thereby stimulating the MAS and improving the cerebral energy balance. With an understanding of a) how ammonia interferes with cerebral energy metabolism and b) how the brain attempts to maintain nitrogen homeostasis it may be possible to suggest improved therapeutic interventions in patients with liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK016739-18
Application #
3225646
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1978-01-01
Project End
1991-12-31
Budget Start
1990-01-01
Budget End
1991-12-31
Support Year
18
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Cruz, Nancy F; Dienel, Gerald A; Patrick, Patricia A et al. (2017) Organ Distribution of 13N Following Intravenous Injection of [13N]Ammonia into Portacaval-Shunted Rats. Neurochem Res 42:1683-1696
Cooper, Arthur J L; Jeitner, Thomas M (2016) Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain. Biomolecules 6:
Jeitner, Thomas M; Battaile, Kevin; Cooper, Arthur J L (2015) Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke. Neurochem Res 40:2544-56
Hallen, André; Jamie, Joanne F; Cooper, Arthur J L (2014) Imine reductases: a comparison of glutamate dehydrogenase to ketimine reductases in the brain. Neurochem Res 39:527-41
Jeitner, Thomas M; Cooper, Arthur J L (2014) Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine-relevance to the treatment of neurological diseases. Metab Brain Dis 29:983-9
Toohey, John I; Cooper, Arthur J L (2014) Thiosulfoxide (sulfane) sulfur: new chemistry and new regulatory roles in biology. Molecules 19:12789-813
Cooper, Arthur J L; Kuhara, Tomiko (2014) ?-Ketoglutaramate: an overlooked metabolite of glutamine and a biomarker for hepatic encephalopathy and inborn errors of the urea cycle. Metab Brain Dis 29:991-1006
Dienel, Gerald A; Cruz, Nancy F (2014) Reduced clearance of proteins labeled with diisopropylfluorophosphate in portacaval-shunted rats. Metab Brain Dis 29:1041-52
Cooper, Arthur J L (2013) Quantitative analysis of neurotransmitter pathways under steady state conditions - a perspective. Front Endocrinol (Lausanne) 4:179
Cooper, Arthur J L (2013) Possible treatment of end-stage hyperammonemic encephalopathy by inhibition of glutamine synthetase. Metab Brain Dis 28:119-25

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