Astroglial Response to Liver Failure

  • M. D. Norenberg
Part of the Altschul Symposia Series book series (ALSS, volume 2)

Abstract

The brain is highly dependent on the integrity of other organs for its own function. Organ failure leads to neurological abnormalities often referred to as metabolic encephalopathies. While these encephalopathies are often reversible, permanent changes occur especially when the process has been severe or prolonged. Our laboratory has been particularly interested in the effect of liver failure on the nervous system, a condition referred to as hepatic encephalopathy (HE). It is a disorder in which astroglial changes dominate the histopathology. We have been working on the premise that this disorder may be a primary disorder of astrocytes and that the neuronal dysfunction results from a glial defect. We also believe that a better understanding of this disorder will yield insights into the function of astrocytes and into the CNS consequences of dysfunction of these cells. In this article, I will review recent progress concerning the role of astrocytes in HE especially as it deals with astroglial swelling.

Keywords

Glial Fibrillary Acidic Protein Hepatic Encephalopathy Brain Edema Fulminant Hepatic Failure Cell Volume Regulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Alho, H., Costa, E., Ferrero, P., Fujimoto, M., Cosenza-Murphy, D. and Guidotti, A. (1985) Diazepam binding inhibitor: A neuropeptide located in selected neuronal populations of rat brain. Science 229: 179–182.PubMedCrossRefGoogle Scholar
  2. Alvarez, J., Garcia-Sancho, J., Mollinedo, F. and Sanchez, A. (1989) Intracellular Cat+ potentiates Na+/H+ exchange and cell differentiation induced by phorbol ester in U937 cells. Eur. J. Biochem. 183: 709–714.PubMedCrossRefGoogle Scholar
  3. Anholt, R.R.H., Pedersen, P.L., DeSouza, E.B. and Snyder, S.H. (1986) The peripheral-type benzodiazepine receptor: localization to the mitochondrial outer membrane. J. Biol. Chem. 261: 576–583.PubMedGoogle Scholar
  4. Babcock-Atkinson, E., Norenberg, M.D., Norenberg, L-O.B. and Neary, J.T. (1989) Calcium/calmodulin-dependent protein kinase activity in primary astrocyte cultures. Glia 2: 112–118.PubMedCrossRefGoogle Scholar
  5. Baraldi, M. and Zeneroli, M.L. (1982) Experimental hepatic encephalopathy: changes in the binding of gamma-aminobutyric acid. Science 216: 427–429.PubMedCrossRefGoogle Scholar
  6. Barres, B. A., Chun, L.L.Y. and Corey, D.P. (1989) Calcium current in cortical astrocytes: induction by cAMP and neurotransmitters and permissive effect of serum factors. J. Neurosci. 9: 3169–3175.PubMedGoogle Scholar
  7. Basile, A.S., Hughes, R.D., Harrison, P.M., Murata, Y., Pannell, L., Jones, E.A., Williams, R. and Skolnick, P. (1991) Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. New Engl. J. Med. 325: 473–478.PubMedCrossRefGoogle Scholar
  8. Bender, A.S. and Hertz, L. (1984) Flunitrazepam binding to intact and homogenized astrocytes and neurons in primary cultures. J. Neurochem. 43: 1319–1327.PubMedCrossRefGoogle Scholar
  9. Bender, A.S. and Hertz, L. (1985) Pharmacological evidence that the non-neuronal diazepam bind- ing site in primary cultures of glial cells is associated with a calcium channel. Europ. J. Phamacol. 110: 287–288.CrossRefGoogle Scholar
  10. Bender, A.S. and Hertz, L. (1986) Octadecaneuropeptide (ODN; anxiety peptide) displaces diazepam more potently from astrocytic than from neuronal binding sites. Eur. J. Pharmacol. 132: 335–336.PubMedCrossRefGoogle Scholar
  11. Bender, A.S., Neary, J.T., Blicharska, J., Norenberg, L-O.B. and Norenberg, M.D. (1990) Role of calcium-dependent protein kinases in astrocytic cell volume regulation. Trans. Am. Soc. Neurochem. 21: 214.Google Scholar
  12. Bender, A.S., Neary, J.T., Blicharska, J., Norenberg, L-O.B. and Norenberg, M.D. (1992a) Role of calmodulin and protein kinase C in astrocytic cell volume regulation. J. Neurochem. 58: 1874–1882.PubMedCrossRefGoogle Scholar
  13. Bender, A.S., Neary, J.T. and Norenberg, M.D. (1992b - In Press) Involvement of second messengers and protein phosphorylation in astrocyte swelling. Can. J. Physiol. Pharmacol.Google Scholar
  14. Bender, A.S., Rivera, I.V., Norenberg, M.D. (1992e) Tumor necrosis factor-alpha induces astrocyte swelling. Trans. Amer. Soc. Neurochem. 23: 113.Google Scholar
  15. Brett, J., Gerlach, H., Nawroth, P., Steinberg, S., Godman, G. and Stern, D. (1989) Tumor necrosis factor/cachectin increases permeability of endothelial cell monolayers by a mechanism involving regulatory G Proteins. J. Exp. Med. 169: 1977–1991.PubMedCrossRefGoogle Scholar
  16. Brusilow, S.W. and Traystman, R.J. (1986) Letter to editor. New Engl. J. Med. 314: 786.PubMedGoogle Scholar
  17. Butterworth, R.F., Lavoie, J., Giguere, J.F. and Pomier-Layrargues, G. (1988) Affinities and densities of high affinity (3H) Muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 8: 1084–1088.PubMedCrossRefGoogle Scholar
  18. Canalese, J., Gimson, A.E.S., Mellon, P.J., Davis, M. and Williams, R. (1982) Controlled trial of dexamethasone and mannitol for the cerebral edema of fulminant hepatic failure. Gut 23: 625–629.PubMedCrossRefGoogle Scholar
  19. Chiu, F.-C and Goldman, J.E. (1985) Regulation of glial fibrillary acidic protein (GFAP) expres- sion in CNS development and in pathological states. J. Neuroimmunol. 8: 283–292.PubMedCrossRefGoogle Scholar
  20. Christensen, O. (1987) Mediation of cell volume regulation by Cat+ influx through stretch-activated channels. Nature 330: 66.PubMedCrossRefGoogle Scholar
  21. Cooper, A.J.L. and Plum, F. (1987) Biochemistry and physiology of brain ammonia. Physiol. Rev. 67: 440–519.PubMedGoogle Scholar
  22. Cuilleret, G., Pomier-Layrargues, G., Pons, F., Cadilhac, J. and Michel, H. (1980) Changes in brain catecholamine levels in human cirrhotic hepatic encephalopathy. Gut 21: 565–569.PubMedCrossRefGoogle Scholar
  23. Dillon, D. and Schenker, S. (1972) Cerebrospinal fluid protein concentration in hepatic coma. JAMA 221: 507.PubMedCrossRefGoogle Scholar
  24. Ducis, I., Norenberg, L-O.B. and Norenberg, M.D. (1989) Effect of ammonium chloride on the astrocyte benzodiazepine receptor. Brain Res. 493: 362–365.PubMedCrossRefGoogle Scholar
  25. Ducis, I., Norenberg, L-O.B. and Norenberg, M.D. (1989) Effect of phenol on the astrocyte benzodiazepine receptor. Trans. Amer. Soc. Neurochem. 20: 132.Google Scholar
  26. Ede, R.J. and Williams, R. (1986) Hepatic encephalopathy and cerebral edema. Semin. Liver. Dis. 6: 107–118.PubMedCrossRefGoogle Scholar
  27. Emmer, E., Rood, R.P., Wesolek, J.H., Cohen, M.E., Braithwaite, R.S., Sharp, G.W.G., Murer, H. and Donowitz, M. (1989) Role of calcium and calmodulin in the regulation of the rabbit ileal brush-border membrane Na+/H+ antiporter. J. Membrane Biol. 108: 207–215.CrossRefGoogle Scholar
  28. Falke, L.C. and Mister, S. (1989) Activity of ion channels during volume regulation by clonal NIE115 neuroblastoma cells. Proc. Natl. Acad. Sci. USA 86: 3919–3923.PubMedCrossRefGoogle Scholar
  29. Ferenci, P., Grimm, G., Meryn, S. and Gangl, A. (1989) Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil. Gastroenterology 96: 240–243.PubMedGoogle Scholar
  30. Filipo, V., Minana, M.-D., Azorin, I. and Grisolia, S. (1988) Induction of rat brain tubulin following ammonium ingestion. J. Neurochem. 51: 1041–1045.CrossRefGoogle Scholar
  31. Ganz, R., Swain, M., Traber, P., DalCanto, M., Butterworth, R.F. and Blei, A.T. (1989) Ammonia-induced swelling of rat cerebral cortical slices: Implications for the pathogenesis of brain edema in acute hepatic failure. Metab. Brain Dis. 4: 213.PubMedCrossRefGoogle Scholar
  32. Ghezzi, P. (1992) TNF and the liver. In, Tumor Necrosis Factors: The Molecules and their Emerging Role in Medicine. Beutler B. (Ed), Raven Press, New York, 87–96.Google Scholar
  33. Giguere, J-F., Hamel, E. and Butterworth, R.F. (1989) Increased peripheral benzodiazepine binding sites following portacaval anastomosis in the rat. Neurosci. Absts. 15: 415.Google Scholar
  34. Goldstein, G.W. (1984) The role of brain capillaries in the pathogenesis of hepatic encephalopathy. Hepatology 4: 565–567.PubMedCrossRefGoogle Scholar
  35. Green, J. and Muallem, S. (1989) A common mechanism for activation of the Na+/H+ exchanger by different types of stimuli. FASEB J. 3: 2408–2414.PubMedGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. Gregorios, J.B., Mozes, L.W. and Norenberg, M.D. (1985b) Morphologic effects of ammonia on primary astrocyte cultures. II. Electron microscopic studies. J. Neuropath. Exp. Neurol. 44: 404–414.PubMedCrossRefGoogle Scholar
  38. Gregorios, J.B., Mozes, L.W., Norenberg, L-O.B. and Norenberg, M.D. (1986) Effect of cyclic AMP on ammonia-induced alterations in primary astrocyte cultures. J. Neuropathol. Exp. Neurol. 45: 396–407.PubMedCrossRefGoogle Scholar
  39. Hawkins, R.A. and Jessy, J. (1991) Hyperammonemia does not impair brain function in the abscence of net glutamine synthesis. Biochem J. 277: 697–703.PubMedGoogle Scholar
  40. Hindfelt, B., Plum, F. and Duffy, T.F. (1977) Effect of acute ammonia intoxication on central metabolism in rats with portacaval shunts. J. Clin. Invest. 59: 386–396.PubMedCrossRefGoogle Scholar
  41. Kimura, T. and Budka, H. (1986) Glial fibrillary acidic protein and S-100 protein in human hepatic encephalopathy: immunocytochemical demonstration of dissociation of two glia-associated proteins. Acta Neuropathol. (Berl) 70: 17–21.CrossRefGoogle Scholar
  42. Kleinzeller, A. and Ziyadeh, F.N. (1990) Cell volume regulation in epithelia with emphasis on the role of osmolytes and the cytoskeleton. In, R.K.H. Kinne, E. Kinne-Saffran, and K.W. Beyenbach (Eds.), Comparative Physiology, Vol. 4, Basel, Karger, pp. 59–82.Google Scholar
  43. Klotz, U. and Walker, S. (1989) Flumazenil and HE. Lancet 1: 155–156.PubMedCrossRefGoogle Scholar
  44. Kuriyama, K., Tomono, S., Kishi, M., Mukainaka, T. and Ohkuma, S. (1987) Development of gamma-aminobutyric acid (GABA)ergic neurons in cerebral cortical neurons in primary culture. Brain Res. 416: 7–21.PubMedCrossRefGoogle Scholar
  45. Lavoie, J., Giguere, J.F., Pomier-Layrargues, G. and Butterworth, R.F. (1987) Amino acid changes in autosied brain tissue from cirrhotic patients with hepatic encephalopathy. J. Neurochem. 49: 692–697.PubMedCrossRefGoogle Scholar
  46. Lavoie, J., Layrargues, G.P. and Butterworth, R.F. (1989) Increased densities of peripheral-type benzodiazepine receptors in autopsied brain tissue from alcoholic patients with hepatic encephalopathy. Neurosci. Absts. 15: 415.Google Scholar
  47. Liskowsky, D.R., Norenberg, L-O.B. and Norenberg, M.D. (1986) Effect of ammonia on cyclic AMP production in primary astrocyte cultures. Brain Res. 386: 386–388.PubMedCrossRefGoogle Scholar
  48. Maddison, J.E., Dodd, P.R., Morrison, M. Johnston, G.A.R. and Farrell, G.C. (1987) Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy. Hepatology 7: 621–628.Google Scholar
  49. McCarthy, K.D. and Harden, T.K. (1981) Identification of two benzodiazepine binding sites on cells cultured from rat cerebral cortex. J. Pharm Exp. Ther. 216: 183–191.Google Scholar
  50. Michie, H.R., Manogue, K.R., Spriggs, D.R., Revbhaug, A., O’Dwyyer, S., Dinarello, C.A., Cerami, A., Wolff, S.M. and Wilmore, D.W. (1988) Detection of circulating tumor necrosis factor after endotoxin administration. N. Engl. J. Med. 318: 1481–1486.PubMedCrossRefGoogle Scholar
  51. Monyer, H. and Choi, D.W. (1990) Glucose deprivation neuronal injury in vitro is modified by withdrawal of extracellular glutamine. J. Cereb. Blood Flow Metab. 10: 337–342.PubMedCrossRefGoogle Scholar
  52. Mullen, K.D., Martin, J.V., Mendelson, W.B., Bassett, M.L. and Jones, E.A. (1988) Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy? Lancet 1: 457–459.PubMedCrossRefGoogle Scholar
  53. Neary, J.T., Norenberg, L-O.B. and Norenberg, M.D. (1986) Calcium-activated, phospholipiddependent protein kinase and protein substrates in primary cultures of astrocytes. Brain Res. 385: 420–424.PubMedCrossRefGoogle Scholar
  54. Neary, J.T., van Breemen, C., Forster, E., Norenberg, L-O.B. and Norenberg, M.D. (1989) ATP stimulates calcium influx in primary astrocyte cultures. Biochem. Biophys. Res. Commun. 157: 1410–1416.CrossRefGoogle Scholar
  55. Neary, J.T., Woodson, C., Blicharska, J., Norenberg, L.O.B. and Norenberg MD (1990) Effect of ammonia on calcium homeostasis in primary astrocyte cultures. Brain Res. 524: 231–235.PubMedCrossRefGoogle Scholar
  56. Neary, J.T. and Norenberg, M.D. (1992) Protective effects of extracellular ATP in ammonia toxicity in astrocyte cultures, a model of hepatic encephalopathy. Int. J. Purine and Pyrimidine Res. 3: 93.Google Scholar
  57. Neary, J.T., Whittemore, S.R. and Norenberg, M.D. (1992) Effects of ammonia and ATP on GFAP mRNA in astrocytes. Trans. Amer. Soc. Neurochem. 23: 112.Google Scholar
  58. Norenberg, M.D. (1977) A light and electron microscopic study of experimental portal-systemic (ammonia) encephalopathy. Progression and reversal of the disorder. Lab. Invest. 36: 618–627.PubMedGoogle Scholar
  59. Norenberg, M.D. (1981) The astrocyte in liver disease. In, Advances in Cellular Neurobiology. Fedoroff, S. and Hertz L. (Eds), Academic Press, New York, Vol 2, 303–352.Google Scholar
  60. Norenberg, M.D., Mozes, L.W., Norenberg, L-O.B. and Gregorios, J.B. (1986) Effects of ammonia in primary astrocyte cultures: morphology and biochemical considerations. In, Dynamic Properties of Glia Cells. II. Cellular and Molecular Aspects. Grisar, T., Franck, G., Hertz, L., Norton, W.T., Sensenbrenner, M. and Woodbury D., (Eds), Pergamon, Oxford, 353–362.Google Scholar
  61. Norenberg, M.D. (1988) Hepatic Encephalopathy: Studies with astrocyte cultures. In, The Biochemical Pathology of Astrocytes. Norenberg, M.D., Hertz, L. and Schousboe, A. (Eds), Alan R. Liss, Inc., New York, 451–464.Google Scholar
  62. Norenberg, M.D. (1989) The use of cultured astrocytes in the study of hepatic encephalopathy. In, Hepatic Encephalopathy. Butterworth, R.F. and Layrargues, G.P.(Eds), Humana Press, Clifton, NJ, 215–229.Google Scholar
  63. Norenberg, M.D., Neary, J.T., Norenberg, L-O.B. and McCarthy, M. (1990) Ammonia induced decrease in glial fibrillary acidic protein in cultured astrocytes. J. Neuropathol. Exp. Neurol. 49: 399–405.PubMedCrossRefGoogle Scholar
  64. Norenberg, M.D., Baker, L., Norenberg, L-O.B., Blicharska, J., Bruce-Gregorios, J.H., Neary, J.T. (1991) Ammonia-induced astrocyte swelling in primary culture. Neurochem. Res. 16: 833–836.PubMedCrossRefGoogle Scholar
  65. Norenberg, M.D., Itzhak, Y. (1992 - In Press) Evidence for subtypes of the peripheral-type benzodiazepine receptor in cultured astrocytes. Soc. Neurosci. Abs.Google Scholar
  66. Oh, J.Y., Francis, J.W., Markelonis, G.J. and Oh, T.H. (1992) Interleukin-1 -beta and tumor necrosis factor-alpha increase peripheral-type benzodiazepine binding sites in cultured polygonal astrocytes. J. Neurochem. 58: 2131–2138.PubMedCrossRefGoogle Scholar
  67. Olasmaa, M., Guidotti, A., Costa, E., Rothstein, J.D., Goldman, M.E., Weber, R.J. and Paul, S.M. (1989) Endogenous benzodiazepines in hepatic encephalopathy. Lancet 1: 491–492.PubMedCrossRefGoogle Scholar
  68. Pierce, S.K. and Politis, A.D. (1990) Cat+-activated cell volume recovery mechanisms. Ann. Dev. Physiol. 52: 27–42.CrossRefGoogle Scholar
  69. Plum, F. and Hindfelt, B. (1976). In, P.J. Vinken and G.W.Bruyn (Eds.) Handbook of Clinical Neurology, North-Holland Publ, Amsterdam, vol. 27, pp. 349–377.Google Scholar
  70. Record, C.O. (1991) Neurochemistry of hepatic encephalopathy. Gut 32: 1261–1263.PubMedCrossRefGoogle Scholar
  71. Rothstein, J., McKhann, G., Guarnerf, P., Barbaccia, M., Guidotti, A. and Costa, E. (1988) Diazepam binding inhibitor in hepatic encephalopathy. Soc. Neurosci. Abst. 14: 346.Google Scholar
  72. Schafer, D.F. and Jones, E.A. (1982) Hepatic encephalopathy and the gamma-aminobutyric-acid neurotransmitter system. Lancet is 18–20.Google Scholar
  73. Schoemaker, H., Morelli, M., Deshmukh, P. and Yamamura, H.I. (1982) [3H] Ro5–4864 benzodiazepine binding in the kainate lesioned striatum and Huntington’s diseased basal ganglia. Brain Res. 248: 396–401.Google Scholar
  74. Scollo-Lavizzaire, G. and Steimann, E. (1985) Reversal of hepatic coma by benzodiazepine antagonist (Ro15–1788). Lancet i:1324.Google Scholar
  75. Sher, P.K. and Machen, V.L. (1984) Properties of [3H]diazepam binding sites on cultured murine glia and neurons. Brain Res. 316: 1–6.PubMedGoogle Scholar
  76. Sobel, R.A., DeArmond, S.J., Forno, L.S. and Eng, L.F. (1981) Glial fibrillary acidic protein in hepatic encephalopathy: an immunocytochemical study. J. Neuropathol. Exp. Neurol. 40: 625–632.PubMedCrossRefGoogle Scholar
  77. Solomon, A.K. (1989) Transport pathways: water movement across cell membranes. In,Membrane Transport: People and Ideas. Oxford Univ Press, New York.Google Scholar
  78. Sprengel, R., Werner, P., Seeburg, P.H., Mukhin, A.G., Santi, M.R., Grayson, D.R., Guidotti, A. and Krueger, K.E. (1989) Molecular cloning and expression of cDNA encoding a peripheral-type benzodiazepine receptor. J. Biol. Chem. 264: 20415–20421.PubMedGoogle Scholar
  79. Takahashi, H., Koehler, R.C., Brusilow, S.W. and Traystman, R.J. (1991) Inhibition of glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am. J. Physiol. 261: H825 - H829.PubMedGoogle Scholar
  80. Tominaga, S., Watanabe, A. and Tsuji T. (1991) Synergistic effect of bile acid, endotoxin, and ammonia on brain edema. Metab. Brain Dis. 6: 93–105.CrossRefGoogle Scholar
  81. Traber, P.G., Dal Canto, M., Ganger, D. and Blei, A.T. (1987) Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure. Hepatology 7: 1257–1261.CrossRefGoogle Scholar
  82. Warren, K.S. and Schenker, S. (1964) Effect of an inhibitor of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J. Lab. Clin. Med. 64: 442–449.PubMedGoogle Scholar
  83. Watson, P.A. (1989) Accumulation of cAMP and calcium in S40 mouse lymphoma cells following hyposmotic swelling. J. Biol. Chem. 264: 14735–14740.PubMedGoogle Scholar
  84. Zieve, L. (1987) Pathogenesis of hepatic encephalopathy. Metab. Brain Dis. 2:147–165.PubMedCrossRefGoogle Scholar
  85. Zieve, L. and Lyftogt, C. (1988) Effect of endotoxin and immunoglobulin on the course of experimental hepatic encephalopathy. Metab. Brain Dis. 3: 229–233.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • M. D. Norenberg
    • 1
  1. 1.Laboratory of Neuropathology Veterans Administration Medical Center and Department of PathologyUniversity of Miami/Jackson Memorial HospitalMiamiUSA

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