Metabolic Brain Disease

, Volume 4, Issue 3, pp 213–223 | Cite as

Ammonia-induced swelling of rat cerebral cortical slices: Implications for the pathogenesis of brain edema in acute hepatic failure

  • Robert Ganz
  • Margaret Swain
  • Peter Traber
  • Mauro DalCanto
  • Roger F. Butterworth
  • Andres T. Blei
Original Contributions


The pathogenesis of brain edema in fulminant hepatic failure is incompletely understood. Our previous studies in models of this disease suggest the presence of a cytotoxic mechanism; as cortical astrocytes appeared predominantly swollen, we hypothesized that ammonia, metabolized to glutamine solely within this cell, could play a role in brain water accumulation. We determined ammonia levels in different brain regions of rats after hepatic devascularization, a model previously shown to exhibit brain edema. Concentrations of 2.5 mM were observed in the edematous cerebral cortex. We then added several concentrations of ammonium chloride to the first cortical brain slice, a preparation used to study cytotoxic brain edema. At a final bath concentration of ammonia of 5 and 10 mM, swelling could be detected; a decrease in the space of distribution of inulin was seen at the 10 mM concentration, suggesting intracellular water accumulation. Neuropathologically, astrocytes appeared involved even at subswelling doses of ammonia. Octanoic acid, at a 10 mM concentration, also resulted in demonstrable swelling. Ammonia, at concentrations in the incubation bath that approach the levels seen in anin vivo model of brain edema, results in water accumulation of cortical brain slices. Toxins implicated in the pathogenesis of hepatic encephalopathy, such as ammonia and octanoic acid, may, result in brain water accumulation.

Key words

brain edema ammonia octanoic acid fulminant hepatic failure 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Benjamin, A. M., Okamoto, K., and Quastel, J. H. (1978). Effects of ammonia ions on spontaneous action potentials and on contents of sodium, potassium, ammonium and chloride ions in brains in vitro.J. Neurochem. 30: 131–143.Google Scholar
  2. Brunner, G., Windus, G., and Schmidt, F. W. (1984). Intracranial pressure and brain edema in experimental hyperammonemia. InAdvances in Hepatic Encephalopathy and Urea Cycle Diseases, Klinberger, G. (ed.), Karger, Basel, pp. 325–330.Google Scholar
  3. Chan, P. H., and Fishman, R. A. (1978). Brain edema: Induction in cortical slices by polyunsaturated fatty acids.Science 201: 358–360.Google Scholar
  4. Chan, P. C., Fishman, R. A., Lee, J. L., and Quan, S. C. (1980). Arachidonic acid-induced swelling in incubated rat brain cortical slices. Effect of bovine serum albumin.Neurochem. Res. 5: 629–640.Google Scholar
  5. Cohen, S. R. (1969). A rapid, sensitive, semimicro gel filtration procedure for detecting and removing low molecular weight fragments from3H or14C-labeled inulin.Anal. Biochem. 31: 539–544.Google Scholar
  6. Cooper, A. J. L., Mora, S. N., Cruz, N. F., and Gelbard, A. S. (1985). Cerebral ammonia metabolism in hyperammonemic rats.J. Neurochem. 44: 1716–1723.Google Scholar
  7. Dahl, D. R. (1968). Short chain fatty acid inhibition of rat brain Na-K adenosine triphosphatase.J. Neurochem. 15: 815–820.Google Scholar
  8. Dunnett, C. W. (1955). A multiple comparison procedure for comparing several treatments with a control.J. Am. Stat. Assoc. 50: 1096–1121.Google Scholar
  9. Ede, R., Gove, C. D., Hughes, R. D., Marshall, W. and Williams, R. (1987). Reduced brain Na+, K+-ATPase activity in rats with galactosamine-induced hepatic failure: relationship to encephalopathy and cerebral oedema.Clin. Sci. 72: 365–371.Google Scholar
  10. Giguere, J. F., and Butterworth, R. F. (1981). Amino acid changes in regions of the CNS in relation to function in experimental portal-systemic encephalopathy.Neurochem. Res. 9: 1309–1311.Google Scholar
  11. Gregorios, J. B., Mozes, L. W., Norenberg, L.-O. B., and Norenberg, M. D. (1985a). Morphologic effects of ammonia on primary astrocyte cultures. I. Light microscopic studies.J. Neuropathol. Exp. Neurol. 44: 397–403.Google Scholar
  12. Gregorios, J. B., Mozes, L. W., and Norenberg, M. D. (1985b). Morphologic effects of ammonia on primary astrocyte cultures. II. Electron microscopic studies.J. Neuropathol. Exp. Neurol. 44: 404–414.Google Scholar
  13. Harvey, A., and McIlwain, H. (1969). Electrical phenomena and isolated tissues from the brain. In Lajtha, A. (ed.),Handbook of Neurochemistry, Plenum Press, New York, pp. 115–121.Google Scholar
  14. Holmin, T., and Siesjö, B. K. (1974). The effect of portacaval anastomosis upon the energy state and upon acid-base parameters of the rat brain.J. Neurochem. 22: 403–412.Google Scholar
  15. Horowitz, M. E., Schafer, D. F., Molnar, P., Jones, E. A., Blasberg, L. E., Patlak, C. S., Waggoner, J., and Fernstermacher, J. D. (1983). Increased blood-brain transfer in a rabbit model of acute liver failure.Gastroenterology 84: 1003–1011.Google Scholar
  16. Jones, E. A., and Schafer, D. F. (1981) Fulminant hepatic failure. In Zakim, D., and Boyer, T. A., (eds.),Hepatology, W. B. Saunders, Philadelphia, pp. 415–445.Google Scholar
  17. Kempski, O., Chaussy, L., Gross, U., Zimmer, M., and Baethmann, A. (1983). Volume regulation and metabolism of suspended C6 glioma cells: An in vitro model to study cytotoxic brain edema.Brain Res. 279: 217–228.Google Scholar
  18. Kindt, G. W., Brock, M., Altenau, L. L., and Poll, W. (1977). Blood/brain barrier and brain oedema in ammonia intoxication.Lancet 1: 201.Google Scholar
  19. Klatzo, I. (1967). Neuropathological aspects of brain edema.J. Neuropathol. Exp. Neurol. 26: 1–14.Google Scholar
  20. Kun, E., and Kearney, E. B. (1974). Ammonia. InMethods of Enzymatic Analysis, Berkmeyer, H. V. (ed.), Academic Press, New York, pp. 1802–1806.Google Scholar
  21. Kvamme, E., and Lenda, K. (1982). Regulation of glutaminase by exogenous glutamate, ammonia and 2-oxoglutarate in synaptosomal enriched preparation from rat brain.Neurochem. Res. 7: 667–678.Google Scholar
  22. Lo, W. D., Ennis, S. R., Goldstein, G. W., McNeely, D. L., and Betz, A. L. (1987). The effects of galactosamine-induced hepatic failure upon blood-brain barrier permeability.Hepatology 7: 452–456.Google Scholar
  23. Mans, A. M., Saunders, S. J., Kirsch, R. E., and Biebuyck, J. F. (1979). Correlation of plasma and brain aminoacid and putative neurotransmitter alterations during acute hepatic coma in the rat.J. Neurochem. 32: 285–292.Google Scholar
  24. Moller, M., Hertz, L., Molgaard, K., and Lund-Andersen, H. (1974). Concordance between morphological and biochemical estimates of fluid spaces in rat brain cortex.Exp. Brain Res. 22: 299–314.Google Scholar
  25. Norenberg, M. D. (1981). The astroeyte in liver disease.Adv. Cell Neurobiol. 2: 303–352.Google Scholar
  26. O'Grady, J. G., Gimson, A. E. S., O'Brien, C. J., Pucknell, A., Hughes, R. D., and Williams, R. (1988). Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure.Gastroenterology 94: 1186–1191.Google Scholar
  27. Record, C. O., Buxton, B., Chase, R. A., Curzon, G., Murray-Lyon, I. M., and Williams, R. (1976). Plasma and brain aminoacids in fulminant hepatic failure and their relationship to hepatic encephalopathy.Eur. J. Clin. Invest. 6: 387–394.Google Scholar
  28. Seda, H. W. M., Hughes, R. D., Grove, C. D., and Williams, R. (1984). Inhibition of rat brain Na+-K+ ATPase activity by serum from patients with fulminant hepatic failure.Hepatology 4: 74–79.Google Scholar
  29. Traber, P. G., Ganger, D. R., and Blei, A. T. (1986). Brain edema in rabbits with galactosamine-induced fulminant hepatitis: regional differences and effects on intracranial pressure.Gastroenterology 91: 1347–56.Google Scholar
  30. Traber, P. G., DalCanto, M., Ganger, D. R., and Blei, A. T. (1987). Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure: Ultrastructure and integrity of the blood-brain barrier.Hepatology 7: 1272–1277.Google Scholar
  31. Traber, P. G., DalCanto, M., Ganger, D. R., and Blei, A. T. (1989). Effect of temperature on brain edema and encephalopathy in the rat after hepatic devascularization.Gastroenterology 96: 885–891.Google Scholar
  32. Trauner, D. A., and Adams, H. (1981). Intracranial pressure elevations during octanoate infusions in rabbits: An experimental model of Reye's syndrome.Pediat. Res. 15: 1097–1099.Google Scholar
  33. VanGelden, N. M. (1983). Metabolic interactions between neurons and astroglia: Glutamine synthetase, carbonic anhydrase and water balance. In Ward, A. (ed.),Basic Mechanisms of Neuronal Hyperexcitability, A. L. Liss, New York, pp. 5–29.Google Scholar
  34. Walz, W. (1988). Analysis of ion fluxes and fluid compartmentation in brain slices. In Boulton, A. B., Baker, G. B., and Walz, W. (eds.),Neuronal Microenvironment, Humana, Clifton, N. J., pp. 421–440.Google Scholar
  35. Zieve, F. L., Zieve, L., Doizaki, W. M., and Gilsdorf, R. B. (1974). Synergism between ammonia and fatty acids in the production of coma: Implications for hepatic coma.J. Pharmacol. Exp. Ther. 191: 10–16.Google Scholar

Copyright information

© Plenum Publishing Corporation 1989

Authors and Affiliations

  • Robert Ganz
    • 1
  • Margaret Swain
    • 3
  • Peter Traber
    • 1
  • Mauro DalCanto
    • 2
  • Roger F. Butterworth
    • 3
  • Andres T. Blei
    • 1
  1. 1.Department of MedicineLakeside VA Medical Center and Northwestern UniversityChicago
  2. 2.Department of NeuropathologyLakeside VA Medical Center and Northwestern UniversityChicago
  3. 3.Laboratory of Neurochemistry, “André Viallet” Clinical Research CenterHôpital St. Luc and University of MontrealMontreal

Personalised recommendations