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Adaptive decreases in amino acids (taurine in particular), creatine, and electrolytes prevent cerebral edema in chronically hyponatremic mice: Rapid correction (experimental model of central pontine myelinolysis) causes dehydration and shrinkage of brain

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Abstract

The experimental model of central pontine myelinolysis—chronic (4-day) hyponatremia induced by daily injections of hypotonic dextrose solutions and vasopressin followed by rapid correction with saline—was used in young fasted and thirsted mice. In normal controls, chronic fasting and thirsting lowered plasma and brain glucose levels and cerebral glycolytic and tricarboxylic acid cycle metabolic fluxes. The fasting state had little effect on brain amino acids. Clinically, the animals became semistuporous; about one-third died. Chronic hyponatremia in fasted mice almost tripled the plasma glucose concentrations and increased the brain carbohydrate reserve. Levels of other brain glycolytic and Krebs citric acid cycle intermediates were similar to those of controls. Severe hyponatremia and hypoosmolality induced profound decreases in levels of brain electrolytes, amino acids (especially taurine), and creatine. These changes permitted a new osmotic balance between blood and brain and a normal brain water content. The behavior and mortality of the hyponatremic animals were not different from those of the fasted control mice. Correction of hyponatremia to normonatremic levels over a 9-hr period returned brain Na+ and K+ levels to normal but the contents of the measured amino acids and creatine were still reduced one-third or more. As a result, treatment produced a significant degree of dehydration and shrinkage of the brain. The findings stress the importance of amino acids (taurine in particular) and creatine levels, as well as electrolytes, in brain osmoregulation and suggest a role for an osmotic disequilibrium—blood osmolality higher than brain—in the production of brain lesions following rapid correction of chronic hyponatremia in animals and possibly in humans. Replenishment of depleted brain K+ and amino acid levels, as well as slow elevation of the chronically depressed level of plasma Na+, is recommended.

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References

  • Adams, R. D., Victor, M., and Mancall, E. L. (1959). Central pontine myelinolysis: A hitherto undescribed disease occurring in alcoholic and malnourished patients.Arch. Neurol. Psychol. 81: 154–172.

    Google Scholar 

  • Arieff, A. I. (1986). Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women.N. Engl. J. Med. 314: 1529–1535.

    Google Scholar 

  • Arieff, A. I., Kleeman, C. R., Keusherian, A., and Bagdoyan, H. (1972). Brain tissue osmolality: Method of determination and variations in hyper- and hypo-osmolar states.J. Lab. Clin. Med. 79: 334–343.

    Google Scholar 

  • Arieff, A. I., Guisado, R., and Lazarowitz, V. C. (1977). Pathophysiology of hyperosmolar states. In Andreoli, T. E., Grantham, J. J., and Rector, F. C., Jr. (eds.),Disturbances in Body Fluid Osmolality, American Physiological Society, Bethesda, Md., pp. 227–250.

    Google Scholar 

  • Atkinson, D. E. (1968). The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers.Biochemistry 7: 4030–4034.

    Google Scholar 

  • Ayus, J. C., Krothapalli, R. K., and Armstrong, D. L. (1985a). Rapid correction of severe hyponatremia in the rat: histologic changes in the brain.Am. J. Physiol. 248: F711–F719.

    Google Scholar 

  • Ayus, J. C., Krothapalli, R. K., and Arieff, A. I. (1985b). Changing concepts in treatment of severe symptomatic hyponatremia. Rapid correction and possible relation to central pontine myelinolysis.Am. J. Med. 78: 897–902.

    Google Scholar 

  • Baethmann, A., and Van Harreveld, A. (1973). Water and electrolyte distribution in gray matter rendered edematous with a metabolic inhibitor.J. Neuropathol. Exp. Neurol. 32: 408–423.

    Google Scholar 

  • Bennett, J. P., Jr., Logan, W. J., and Snyder, S. H. (1973). Amino acids as central nervous transmitters: The influence of ions, amino acid analogues, and ontogeny on transport systems for L-glutamic and L-aspartic acids and glycine into central nervous synaptosomes of the rat.J. Neurochem. 21: 1533–1550.

    Google Scholar 

  • Berger, S. J., Carter, J. A., and Lowry, O. H. (1975). An enzymatic method for glycine.Anal. Biochem. 65: 232–240.

    Google Scholar 

  • Burcar, P. J., Norenberg, M. D., and Yarnell, P. R. (1977). Hyponatremia and central pontine myelinolysis.Neurology 27: 223–226.

    Google Scholar 

  • Cadman, T. E., and Rorke, L. B. (1969). Central pontine myelinolysis in childhood and adolescence.Arch. Dis. Childhood 44: 342–350.

    Google Scholar 

  • Chan, P. H., and Fishman, R. A. (1979). Elevation of rat brain amino acids, ammonia and idiogenic osmoles induced by hyperosmolality.Brain Res. 161: 293–301.

    Google Scholar 

  • Dodge, P. R., Crawford, J. D., and Probst, J. H. (1960). Studies in experimental water intoxication.Arch. Neurol. 3: 513–529.

    Google Scholar 

  • Duffy, T. E., Cavazzuti, M., Cruz, N. F., and Sokoloff, L. (1982). Local cerebral glucose metabolism in newborn dogs: Effects of hypoxia and halothane anesthesia.Ann. Neurol. 11: 233–246.

    Google Scholar 

  • Elliott, K. A. C., and Jasper, H. (1949). Measurement of experimentally induced brain swelling and shrinkage.Am. J. Physiol. 157: 122–129.

    Google Scholar 

  • Fawcett, J. K., and Scott, J. E. (1960). A rapid and precise method for the determination of urea.J. Clin. Pathol. 13, 156–159.

    Google Scholar 

  • Fellman, J. H., Roth, E. S., and Fujita, T. S. (1978). Taurine is not metabolized to isethionate in mammalian tissue. In Barbeau, A., and Huxtable, R. J. (eds.),Taurine and Neurological Disorders, Raven Press, New York, pp. 19–24.

    Google Scholar 

  • Flear, T. G., and Gill, G. V. (1981). Hyponatremia: Mechanisms and management.Lancet 2: 26–31.

    Google Scholar 

  • Florkin, M., and Schoffeniels, E. (1965). Euryhalinity and the concept of physiological radiation. In Munday, K. A. (ed.),Studies in Comparative Biochemistry, Pergamon Press, Oxford, pp. 6–40.

    Google Scholar 

  • Folbergrová, J., Passonneau, J. V., Lowry, O. H., and Schulz, D. W. (1969). Glycogen, ammonia and related metabolites in the brain during seizures evoked by methionine sulphoximine.J. Neurochem. 16: 191–203.

    Google Scholar 

  • Goldberg, N. D., Passonneau, J. V., and Lowry, O. H. (1966). Effects of changes in brain metabolism on the levels of citric acid cycle intermediates.J. Biol. Chem. 241: 3997–4003.

    Google Scholar 

  • Hirsch, H. E., and Robins, E. (1962). Distribution of γ-aminobutyric acid in the layers of the cerebral and cerebellar cortex. Implications for its physiological role.J. Neurochem. 9: 63–70.

    Google Scholar 

  • Holowach-Thurston, J., Hauhart, R. E., Jones, E. M., Ikossi, M. G., and Pierce, R. W. (1973). Decrease in brain glucose in anoxia in spite of elevated plasma glucose levels.Pediat. Res. 7: 691–695.

    Google Scholar 

  • Illowsky, B., and Laureno, R. (1984). Uncorrected hyponatremia does not cause myelinolysis.Kidney Int. 25: 168 (abstract).

    Google Scholar 

  • Ing, T. S., Wu, C., Rosenberg, J. C., Ng, P. S. Y., Su, W., Bernard, A. A., and Wilson, R. F. (1977). Cerebrospinal fluid changes in experimental cardiopulmonary bypass using hemodilution with glucose water.Neurology 27: 85–89.

    Google Scholar 

  • Klavins, J. V. (1963). Central pontine myelinolysis.J. Neuropathol. Exp. Neurol. 22: 302–317.

    Google Scholar 

  • Kleinschmidt-DeMasters, B. K., and Norenberg, M. D. (1981). Rapid correction of hyponatremia causes demyelination: Relation to central pontine myelinolysis.Science 211: 1068–1070.

    Google Scholar 

  • Kleinschmidt-DeMasters, B. K., and Norenberg, M. D. (1982). Neuropathologic observations in electrolyte-induced myelinolysis in the rat.J. Neuropathol. Exp. Neurol. 41, 67–80.

    Google Scholar 

  • Lajtha, A., and Sershen, H. (1975). Inhibition of amino acid uptake by the absence of Na+ in slices of brain.J. Neurochem. 24: 667–672.

    Google Scholar 

  • Laureno, R. (1980). Experimental pontine and extrapontine myelinolysis.Trans. Am. Neurol. Assoc. 105: 354–358.

    Google Scholar 

  • Laureno, R. (1983). Central pontine myelinolysis following rapid correction of hyponatremia.Ann. Neurol. 13: 232–242.

    Google Scholar 

  • Ljunggren, B., Schutz, H., and Siesjö, B. K. (1974). Changes in energy state and acid-base parameters of the rat brain during complete compression ischemia.Brain Res. 73, 277–289.

    Google Scholar 

  • Lockwood, A. H. (1975). Acute and chronic hyperosmolality: Effects on cerebral amino acids and energy metabolism.Arch. Neurol. 32: 62–64.

    Google Scholar 

  • Lowry, O. H., and Passonneau, J. V. (1972).A Flexible System of Enzymatic Analysis, Academic Press, New York, pp. 120–128, 146–222.

    Google Scholar 

  • Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193: 265–275.

    Google Scholar 

  • Lowry, O. H., Passonneau, J. V., Hasselberger, F. X., and Schulz, D. W. (1964). Effect on ischemia on known substrates and cofactors of the glycolytic pathway in brain.J. Biol. Chem. 239: 18–30.

    Google Scholar 

  • Luse, S. A., and Harris, B. (1961). Brain ultrastructure in hydration and dehydration.Arch. Neurol. 4: 139–152.

    Google Scholar 

  • Margolis, R. K., and Lajtha, A. (1968). Ion dependence of amino acid uptake in brain slices.Biochim. Biophys. Acta 163: 374–385.

    Google Scholar 

  • Measures, J. C. (1975). Role of amino acids in osmoregulation of non-halophilic bacteria.Nature 257: 398–400.

    Google Scholar 

  • Messert, B., Orrison, W. W., Hawkins, M. J., and Quaglieri, C. E. (1979). Central pontine myelinolysis. Considerations on etiology, diagnosis, and treatment.Neurology 29: 147–160.

    Google Scholar 

  • Narins, R. G. (1986). Therapy of hyponatremia. Does haste make waste?N. Engl. J. Med. 314: 1573–1575.

    Google Scholar 

  • Norenberg, M. D. (1981). Ultrastructural observations in electrolyte-induced myelinolysis (Abstract).J. Neuropath. Exp. Neurol. 40: 319.

    Google Scholar 

  • Norenberg, M. D. (1981). Ultrastructural observations in electrolyte-induced myelinolysis.J. Neuropath. Exp. Neurol. 40: 319 (abstract).

    Google Scholar 

  • Olney, J. W. (1978). Neurotoxicity of excitatory amino acids. In McGeer, E., Olney, J. W., and McGeer, P. (eds.),Kainic Acid as a Tool in Neurobiology, Raven Press, New York, pp. 95–121.

    Google Scholar 

  • Olney, J. W. (1982). The toxic effects of glutamate and related compounds in the retina and the brain.Retina 2: 341–359.

    Google Scholar 

  • Orr, H. T., Cohen, A. I., and Lowry, O. H. (1976). The distribution of taurine in the vertebrate retina.J. Neurochem. 26: 609–611.

    Google Scholar 

  • Passonneau, J. V., and Lauderdale, V. R. (1974). A comparison of three methods of glycogen measurement in tissues.Anal. Biochem. 60: 405–412.

    Google Scholar 

  • Rottenberg, D. A., Hurwitz, B. J., and Posner, J. B. (1977). The effect of oral glycerol on intraventricular pressure in man.Neurology 27: 600–608.

    Google Scholar 

  • Rymer, M. M., and Fishman, R. A. (1973). Protective adaptation of brain to water intoxication.Arch. Neurol. 28: 49–54.

    Google Scholar 

  • Shank, R. P., and Baxter, C. F. (1973). Metabolism of glucose, amino acids and some related metabolites in the brain of toads (Bufo Boreas) adapted to fresh water or hyperosmotic environments.J. Neurochem. 21: 301–313.

    Google Scholar 

  • Söling, H.-D., and Seufert, C.-D. (eds.) (1978).Biochemical and Clinical Aspects of Ketone Body Metabolism, Georg Thieme, Stuttgart, pp. 254–256.

    Google Scholar 

  • Sterns, R. H., Riggs, J. E., and Schochet, S. S., Jr. (1986). Osmotic demyelination syndrome following correction of hyponatremia.N. Engl. J. Med. 314: 1535–1542.

    Google Scholar 

  • Stewart, G. R., and Lee, J. A. (1974). The role of proline accumulation in halophytes.Planta (Berl.) 120: 279–289.

    Google Scholar 

  • Tachiki, K. H., and Baxter, C. F. (1980). Role of plasma amino acids in adapting brain to a hyperosmotic environment.Trans. Am. Soc. Neurochem. 11(1): 222.

    Google Scholar 

  • Thurston, J. H., and McDougal, D. B., Jr. (1969). Effect of ischemia on metabolism of the brain of the newborn mouse.Am. J. Physiol. 216: 348–352.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., Jones, E. M., and Ater, J. L. (1975a). Effects of alloxan diabetes, antiinsulin serum diabetes, and non-diabetic dehydration on brain carbohydrate and energy metabolism in young mice.J. Biol. Chem. 250: 1751–1758.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., Jones, E. M., and Ater, J. L. (1975b). Effect of salt and water loading on carbohydrate and energy metabolism and levels of selected amino acids in the brains of young mice.J. Neurochem. 24: 953–957.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., and Dirgo, J. A. (1976). Insulin and brain metabolism: Absence of direct action of insulin on K+ and Na+ transport in mouse brain.Diabetes 25: 758–763.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., and Dirgo, J. A. (1978). Hyperglycemia, hypoinsulinemia, and hyperglucagonemia in acute water intoxication.Diabetes 27: 61–63.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., and Dirgo, J. A. (1980). Taurine: A role in osmotic regulation of mammalian brain and possible clinical significance.Life Sci. 26: 1561–1568.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., and Dirgo, J. A. (1981). Effects of a single therapeutic dose of glycerol on cerebral metabolism in the brains of young mice: Possible increase in brain glucose transport and glucose utilization.J. Neurochem. 36: 830–838.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., and Schulz, D. W. (1983). Effect of chronic hypernatremic dehydration and rapid rehydration on brain carbohydrate, energy, and amino acid metabolism in weanling mice.J. Neurochem. 40: 240–245.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., and Dirgo, J. A. (1986a). Effects of acute hyperosmolar NaCl or urea on brain H2O, Na+, K+, carbohydrate, and amino acid metabolism in weanling mice: NaCl induces insulin secretion and hypoglycemia.Metab. Brain Dis. 1: 129–146.

    Google Scholar 

  • Thurston, J. H., Hauhart, R. E., and Schiro, J. A. (1986b).β-Hydroxybutyrate reverses insulin-induced hypoglycemic coma in suckling-weanling mice despite low blood and brain glucose levels.Metab. Brain Dis. 1: 63–82.

    Google Scholar 

  • Tukey, J. W. (1953).The Problem of Multiple Comparisons, Ditto, Princeton University, Princeton, N.J. [Cited by Kirk, R. E. (1968).Experimental Design: Procedures for the Behavioral Sciences, Brooks/Cole, Belmont, Calif, pp. 69–98].

    Google Scholar 

  • Verbalis, J. G., Baldwin, E. F., and Robinson, A. G. (1986). Osmotic regulation of plasma vasopressin and oxytocin after sustained hyponatremia.Am. J. Physiol. 250: R444–R451.

    Google Scholar 

  • Wasterlain, C. G., and Torack, R. M. (1968). Cerebral edema in water intoxication. II. An ultrastructural study.Arch. Neurol. 19: 79–87.

    Google Scholar 

  • Williamson, D. H., Mellanby, J., and Krebs, H. A. (1962). Enzymic determination of D(-)-β-hydroxybutyric acid and acetoacetic acid in blood.Biochem. J. 82: 90–98.

    Google Scholar 

  • Young, R. L., and Lowry, O. H. (1966). Quantitative methods for measuring the histochemical distribution of alanine, glutamate and glutamine in brain.J. Neurochem. 13: 785–793.

    Google Scholar 

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  1. The Edward Mallinckrodt Department of Pediatrics and Department of Neurology and Neurological Surgery (Neurology), Washington University School of Medicine, Children's Hospital, 63110, St. Louis, Missouri

    Jean Holowach Thurston, Richard E. Hauhart & James S. Nelson

  2. Department of Pathology, Washington University School of Medicine, 63110, St. Louis, Missouri

    James S. Nelson

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  1. Jean Holowach Thurston
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  2. Richard E. Hauhart
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  3. James S. Nelson
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Thurston, J.H., Hauhart, R.E. & Nelson, J.S. Adaptive decreases in amino acids (taurine in particular), creatine, and electrolytes prevent cerebral edema in chronically hyponatremic mice: Rapid correction (experimental model of central pontine myelinolysis) causes dehydration and shrinkage of brain. Metab Brain Dis 2, 223–241 (1987). https://doi.org/10.1007/BF00999694

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