The goal of this research is to define some of the physiological and biochemical changes which occur during chronic hepatic encephalopathy. This is a necessary first step toward defining objective criteria by which therapeutic measures can be judged. Carefully characterized rats with portal-systemic shunts will be used as a model of chronic encephalopathy. The supply of essential nutrients to brain is determined by the plasma concentrations and the transport systems which facilitate their passage across the blood-brain barrier. In normal animals, the blood-brain barrier mediates a delicate balance between supply and need, but following portal-systemic shunting, the permeability characteristics of several transport systems are markedly altered. This is believed to be of etiologic significance to the development of encephalopathy since brain receives an excess of some nutrients but may be almost starved of others. Among the essential nutrients to be studied are neutral and basic amino acids, glucose, choline, purines and nucleosides. The time course of specific changes in regional transport will be determined. The results will be compared to changes in neural function as determined by measuring glucose utilization using [2-14C]glucose in either whole brain or at the structural level. The mechanism of the blood-brain barrier changes may be closely related to metabolism of NH4+ to glutamine. This will be studied in vivo by manipulating blood NH4 concentrations and cerebral glutamine content in chronic and acute experiments. Reduction of basic amino acid influx is so extreme that protein synthesis may be retarded. This possibility will be examined in whole brain and in individual structures by determination of the rate of protein synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS016389-05
Application #
3396855
Study Section
Neurology A Study Section (NEUA)
Project Start
1979-12-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Lee, W J; Hawkins, R A; Vina, J R et al. (1998) Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal. Am J Physiol 274:C1101-7
Hawkins, P A; DeJoseph, M R; Hawkins, R A (1998) Diurnal rhythm returns to normal after elimination of portacaval shunting. Am J Physiol 274:E426-31
Hawkins, P A; DeJoseph, M R; Vina, J R et al. (1996) Comparison of the metabolic disturbances caused by end-to-side and side-to-side portacaval shunts. J Appl Physiol 80:885-91
Hawkins, P A; DeJoseph, M R; Hawkins, R A (1996) Reversal of portacaval shunting normalizes brain energy consumption in most brain structures. Am J Physiol 271:E1015-20
Hawkins, P A; DeJoseph, M R; Hawkins, R A (1996) Eliminating metabolic abnormalities of portacaval shunting by restoring normal liver blood flow. Am J Physiol 270:E1037-42
Sanchez del Pino, M M; Hawkins, R A; Peterson, D R (1995) Biochemical discrimination between luminal and abluminal enzyme and transport activities of the blood-brain barrier. J Biol Chem 270:14907-12
Sanchez del Pino, M M; Peterson, D R; Hawkins, R A (1995) Neutral amino acid transport characterization of isolated luminal and abluminal membranes of the blood-brain barrier. J Biol Chem 270:14913-8
Hawkins, R A; Mans, A M (1994) Brain metabolism in encephalopathy caused by hyperammonemia. Adv Exp Med Biol 368:11-21
Hawkins, R A; Jessy, J; Mans, A M et al. (1994) Neomycin reduces the intestinal production of ammonia from glutamine. Adv Exp Med Biol 368:125-34
Hawkins, R A; Hawkins, P A; Mans, A M et al. (1994) Optimizing the measurement of regional cerebral glucose consumption with [6-14C]glucose. J Neurosci Methods 54:49-62

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