Abstract
Sustained hyperammonemia resulting from portocaval anastomosis (PCA) in the rat, is accompanied by neurological symptoms and reversible morphological changes in brain, the nature and distribution of which suggest selective vulnerability of certain brain structures. the present study was initiated to investigate the effects of increasing CNS ammonia on the distribution of amino acids in regions of the rat brain in relation to the degree of neurological impairment in PCA rats. Four weeks following PCA, rats were administered ammonium acetate (5.2 mmol/kg, i.p.) to precipitate neurological symptoms of encephalopathy which included diminished locomotor activity, loss of hindlimb extension and righting reflexes and ultimately coma. At various stages during the development of encephalopathy, rats were sacrificed and the amino acids glutamine, glutamate and aspartate measured simultaneously, using a sensitive double-isotope dansyl microassay. Homogenates of the following regions of the CNS were assayed: cerebral cortex, hippocampus, striatum, midbrain, hypothalamus, cerebellum, medulla-pons, spinal cord (gray matter) and spinal cord (white matter). Sustained hyperammonemia associated with PCA alone resulted in a non-uniform 2–4 fold increase of glutamine in all regions of the CNS. Glutamate, on the other hand, was selectively increased in striatum and cerebellum, two regions of brain shown to exhibit early morphologically-characterised astrocytic abnormalities in rats with PCA. Onset of severe neurological dysfunction was accompanied by significantly decreased glutamine and glutamate in striatum and cerebellum. Thus, sustained hyperammonemia in association with portocaval shunting results in region-selective effects with respect to glutamine-glutamate metabolism in the CNS.
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Plum, F., andHindfelt, B. 1976. The neurological complications of liver disease. Pages 349–377,in Vinken, P. J., andBruyn, G. W. (eds.), Metabolic and Deficiency Diseases of the Nervous System, Part I, American Elsevier, New York.
Ehrlich, M., Plum, F., andDuffy, T. E. 1980. Blood and brain ammonia concentrations after portocaval anastomosis-effects of acute ammonia loading. J. Neurochem. 34:1538–1542.
Hindfelt, B., Plum, F., andDuffy, T. E. 1977. Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J. Clin. Invest. 59:386–396.
Holmin, T., andSiesjo, B. K. 1974. The effect of porta-caval anastomosis upon the energy state and upon acid-base parameters of the rat brain. J. Neurochem. 22:403–412.
Norenberg, M. D. 1977. A light and electron microscopic study of experimental portalsystemic (ammonia) encephalopathy. Lab. Invest. 36:618–627.
Lee, S. H., andFisher, B. 1961. Portacaval shunt in the rat. Surgery 50:668–672.
Bucci, L., Cardelli, M., Chiavarelli, R., Massotti, M., andMorisi, G. 1980. Behavioral, electroencephalographic and biochemical changes in porta-caval shunted rats. Int. J. Neurosci. 10:129–134.
Lee, S. H., Chandler, J. G., Broelsch, C. E., Flamant, Y. M., andOrloff, M. J. 1974. Portal-systemic anastomosis in the rat. J. Surg. Res. 17:53–73.
Jolicoeur, F. B., Rondeau, D. B., Hamel, E., Butterworth, R. F., andBarbeau, A. 1979. Measurement of ataxia and related neurological signs in the rat. Can. J. Neurol. Sci. 6:209–215.
Glowinski, J., andIversen, L. L. 1966. Regional studies of catecholamines in the rat brain. I. The disposition of3H-norepinephrine,3H-dopamine and3H-dopa in various regions of the brain. J. Neurochem. 13:655–669.
Butterworth, R. F., Merkel, A. D., andLandreville, F. 1982. Regional amino acid distribution in relation to function in insulin hypoglycaemia. J. Neurochem. 38:1483–1489.
Chapman, A. G., Riley, K., Evans, M. C., andMeldrum, B. S. 1982. Acute effects of sodium valproate and γ-vinyl GABA on regional amino acid metabolism in the rat brain: Incorporation of 2-14C-glucose into amino acids. Neurochem. Res. 7:1089–1105.
Kun, E., andKearney, E. B. 1974. Ammonia. Pages 1802–1806,in Berkmeyer, H. V. (ed.), Methods of Enzymatic Analysis, Academic Press, New York.
Winer, B. J. 1971. Statistical Principles in Experimental Design, McGraw-Hill, New York.
Zanchin, G., Rigotti, P., Dussini, N., Vassanelli, P., andBattistin, L. 1972. Chrebral amino acid levels and uptake in rats after portocaval anastomosis: II. Regional studies in vivo. J. Neurosci. Res. 4:301–310.
Cavanagh, J. B., Lewis, P. D., Blakemore, W. F., andKyu, M. H. 1972. Changes in the cerebellar cortex in rats after portacaval anastomosis. J. Neurol. Sci. 15:13–26.
Zamora, A. J., Cavanagh, J. B., andKyu, M. H. 1973. Ultrastructural responses of the astrocytes to portocaval anastomosis in the rat. J. Neurol. Sci. 18:25–45.
Warbritton, J. D., Geyer, M. A., Jeppsson, B. W., andFischer, J. E. 1979. Behavioral model of early hepatic encephalopathy in rats. Surgical Forum 30:394–396.
Beaubernard, C., Salomon, F., Grange, D., Thangapregassam, M. J., andBismuth, J. 1977. Experimental hepatic encephalopathy. Changes of the level of wakefulness in the rat with portacaval shunt. Biomedicine 27:169–171.
Zieve, L. 1982. Hepatic Encephalopathy. Pages 433–459,in Schiff, E., andSchiff, E. R. (eds.), Diseases of The Liver (5th Ed.), Lippincott, Philadelphia.
Giguère, J. F., andButterworth, R. F. 1982. Glutamic acid abnormalities in the central nervous system in hepatic encephalopathy. Clin. Biochem. 15:95.
Weiser, M., Riederer, P., andKleinberger, G. 1978. Human cerebral free amino acids in hepatic coma. J. Neural Trans. (Suppl.) 14:95–102.
Hamberger, A., Jacobsson, I., Molin, S. O., Nystrom, B., andSandberg, M. 1981. Regulation of giutamate biosynthesis and release by pathophysiological levels of ammonium ions. Pages 115–126,in Di Chiara, G., andGessa, G. L. (eds.), Glutamate as a Neurotransmitter, Raven Press, New York.
Norenberg, M. D. 1979. The distribution of glutamine synthetase in the rat central nervous system. J. Histochem. Cytochem. 27:756–762.
Cooper, A. J. L., Vergara, F., andDuffy, T. E. 1983. Cerebral glutamine synthetase. Pages 77–93,in Hertz, L., Kvamme, E., McGeer, E. G., andSchousboe, A. (eds.), Glutamine, Glutamate and Gaba in the Central Nervous System, Alan R. Liss, New York.
Kvamme, E., andLenda, K. 1982. Regulation of glutaminase by exogenous glutamate, ammonia and 2-oxoglutarate in synaptosomal enriched preparation from rat brain. Neurochem. Res. 7:667–677.
Moroni, F., Lombardi, G., Moneti, G., andCortesini, C. 1983. The release and neosynthesis of glutamic acid are increased in experimental models of hepatic encephalopathy. J. Neurochem. 40:850–854.
Cardelli-Cangiano, P., Cangiano, C., James, J. H., Jeppsson, B., Brenner, W., andFischer, J. E. 1981. Uptake of amino acids by brain microvessels isolated from rats after portacaval anastomosis. J. Neurochem. 36:627–632.
Tossman, U., Eriksson, S., Delin, A., Hagenfeldt, L., Law, D., andUngerstedt, U. 1983. Brain amino acids measured by intracerebral dialysis in portacaval shunted rats. J. Neurochem. 41:1046–1051.
Benjamin, A. M. 1983. Ammonia in metabolic interactions between neurons and glia. Pages 399–414,in Hertz, L., Kvamme, E., McGeer, E. G., andSchousboe, A. (eds.), Glutamine, Glutamate and Gaba in the Central Nervous System, Alan R. Liss, New York.
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Giguère, JF., Butterworth, R.F. Amino acid changes in regions of the CNS in relation to function in experimental portal-systemic encephalopathy. Neurochem Res 9, 1309–1321 (1984). https://doi.org/10.1007/BF00973042
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DOI: https://doi.org/10.1007/BF00973042