Hepatic Encephalopathy: A Primary Astrocytopathy

  • Roger F. Butterworth

26.1 Introduction

Results of neuropathological and molecular biological studies indicate that hepatic encephalopathy (HE) in both acute and chronic liver failure is primarily a disorder of astrocytes. Although neuronal cell death has been described in end-stage liver failure (Butterworth, 2007), its prevalence and severity are variable and generally considered to be insufficient to explain the wide range of neuropsychiatric symptoms that are characteristic of HE. HE is therefore considered to be a classical example of a primary astrocytopathy. This chapter is a critical review of astrocyte morphology and function in HE. The implication of alterations in expression of key astrocyte proteins and astrocyte metabolism are reviewed. Two major new discoveries, namely the presence of vesicular release proteins and of functional N-methyl-d-aspartate (NMDA) receptors on astrocytes have resulted in the need for reinterpretation of previous findings in relation to both neuron–astrocyte and...


Glial Fibrillary Acidic Protein Hepatic Encephalopathy Glutamine Synthetase Acute Liver Failure Glial Fibrillary Acidic Protein Expression 
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.



Acute liver failure


Adenosine 5′-triphosphate


Hepatic encephalopathy


Diazepam binding inhibitor


Excitatory amino acid transporter


Gamma-aminobutyric acid


Glial fibrillary acidic protein


Glutamine synthetase


Isoquinoline binding protein




Lactate dehydrogenase




Nuclear magnetic resonance


Nitric oxide synthase


Inducible NOS


Mitogen-activated protein kinase


Positron emission tomography


peripheral-type benzodiazepine receptor



Studies performed in the author's laboratory were funded by the Canadian Institutes for Health Research (CHIR) and the Canadian Liver Foundation (CLF).


  1. Adams RD, Foley JM (1953) The neurological disorder associated with liver disease. In: Merritt HH, Hare CC, eds. Metabolic and toxic diseases of the nervous system Vol. 32, Williams and Wilkins. Baltimore: pp. 198–237.Google Scholar
  2. Ahboucha S, Butterworth RF (2007) The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy. Neurochem Int 52: 575–587.PubMedCrossRefGoogle Scholar
  3. Ahboucha S, Pomier-Layrargues G, Mamer O, Butterworth RF (2005) Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol 58: 169–170.PubMedCrossRefGoogle Scholar
  4. Ahboucha S, Coyne L, Hirakawa R, Butterworth RF, Halliwell RF (2006) An interaction between benzodiazepines and neuroactive steroids at GABAA receptors in cultured hippocampal neurons. Neurochem Int 48: 703–707.PubMedCrossRefGoogle Scholar
  5. Bates TE, Williams SR, Kauppinen RA, Godian DG (1989) Observation of cerebral metabolites in an animal model of ALF in vivo: 1H and 31P nuclear magnetic resonance study. J Neurochem 53: 102–110.PubMedCrossRefGoogle Scholar
  6. Bélanger M, Desjardins P, Chatauret N, Butterworth RF (2002) Loss of expression of glial fibrillary acidic protein in acute hyperammonemia. Neurochem Int 41: 155–160.PubMedCrossRefGoogle Scholar
  7. Bélanger M, Ahboucha S, Desjardins P, Butterworth RF (2004) Upregulation of peripheral-type (mitochondrial) benzodiazepine receptors in hyperammonemic syndromes: consequences for neuronal excitability. Adv Mol Cell Biol 31: 983–997.CrossRefGoogle Scholar
  8. Bélanger M, Desjardins P, Chatauret N, Butterworth RF (2006) Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure. Glia 53: 557–562.PubMedCrossRefGoogle Scholar
  9. Bender AS, Norenberg MD (1996) Effects of ammonia on l-glutamate uptake in cultured astrocytes. Neurochem Res 21: 567–573.PubMedCrossRefGoogle Scholar
  10. Blei AT (2004) Infection, inflammation and hepatic encephalopathy, synergism redefined. J Hepatol 40: 327–330.PubMedCrossRefGoogle Scholar
  11. Blei AT, Olafsson S, Therrien G, Butterworth RF (1994) Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology 19: 1437–1444.PubMedCrossRefGoogle Scholar
  12. Bosman DK, Buijs CA, van den Haan JG, de Maas MA, Chamuleau RA (1991) The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat. Gastroenterology 101: 772–781.PubMedGoogle Scholar
  13. Butterworth RF (2007) Neuronal cell death in hepatic encephalopathy. Metab Brain Dis 3–4: 291–308.Google Scholar
  14. Butterworth RF, Giguère JF, Michaud J, Lavoie J, Layrargues GP (1987) Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 6: 1–12.PubMedCrossRefGoogle Scholar
  15. Butterworth RF, Tonon M-C, Désy L, Giguère J-F, Vaudry H, Pelletier G (1991) Increased brain content of the endogenous benzodiazepine receptor ligand, octadecaneuropeptide (ODN), following portacaval anastomosis in the rat. Peptides 12: 119–125.PubMedCrossRefGoogle Scholar
  16. Cagnin A, Taylor-Robinson SD, Forton DM, Banati RB (2001) In vivo quantification of cerebral “peripheral benzodiazepine binding site” in minimal hepatic encephalopathy: a [11C]R-PK11195 positron emission tomography study. J Hepatol 34 : (Suppl 1)58.Google Scholar
  17. Casellas P, Galiegue S, Basile AS (2002) Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int 40: 475–486.PubMedCrossRefGoogle Scholar
  18. Chan H, Butterworth RF (2006) Glutamatergic synaptic regulation deficit in liver failure: a review of molecular mechanisms. In: Haüssinger D, Kircheis G, Schliess F, eds. Hepatic encephalopathy and nitrogen metabolism Springer. Dordrecht: pp. 160–170.CrossRefGoogle Scholar
  19. Chan H, Hazell AS, Desjardins P, Butterworth RF (2000) Effects of ammonia on glutamate transporter (GLAST) protein and mRNA in cultured rat cortical astrocytes. Neurochem Int 37: 243–248.PubMedCrossRefGoogle Scholar
  20. Chan H, Bélanger M, Chatauret N, Butterworth RF (2002) Brain lactate accumulation in liver failure and hyperammonemia results from increased lactate dehydrogenase LDH-5 isoform expression and altered LDH enzyme kinetics in astrocytes. Hepatology 36: 628.CrossRefGoogle Scholar
  21. Chan H, Zwingmann C, Pannunzio M, Butterworth RF (2003) Effects of ammonia on high affinity glutamate uptake and glutamate transporter EAAT3 expression in cultured rat cerebellar granule cells. Neurochem Int 43: 137–146.PubMedCrossRefGoogle Scholar
  22. Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a 1H/13C-nuclear magnetic resonance study. Gastroenterology 125: 815–824.PubMedCrossRefGoogle Scholar
  23. Conti F, DeBiasi S, Minelli A, Melone M (1996) Expression of NR1 and NR2A/B subunits of the NMDA receptor in cortical astrocytes. Glia 17: 254–258.PubMedCrossRefGoogle Scholar
  24. Conti F, Barbaresi P, Melone M, Ducati A (1999) Neuronal and glial localization of NR1 and NR2A/B subunits of the NMDA receptor in the human cerebral cortex. Cereb Cortex 9: 110–120.PubMedCrossRefGoogle Scholar
  25. Cornet M, Ubl J, Kolb HA (1993) Cytoskeleton and ion movements during volume regulation in cultured PC12 cells. J Membr Biol 133: 161–170.PubMedGoogle Scholar
  26. Cremer JE, Heath DF, Teal HM, Woods MS, Cavanagh JB (1975) Some dynamic aspect of brain metabolism in rats given a portacaval anastomosis. Neuropathol Appl Neurobiol 3: 293–311.CrossRefGoogle Scholar
  27. Desjardins P, Butterworth RF (2002) The “peripheral-type” benzodiazepine (omega 3) receptor in hyperammonemic disorders. Neurochem Int 41: 109–114.PubMedCrossRefGoogle Scholar
  28. Desjardins P, Rama Rao VK, Michalak A, Rose C, Butterworth RF (1999a) Effect of portacaval anastomosis on glutamine synthetase protein and gene expression in brain, liver and skeletal muscle. Metab Brain Dis 14: 273–282.CrossRefGoogle Scholar
  29. Desjardins P, Bandeira P, Raghavendra Rao VL, Butterworth RF (1999b) Portacaval anastomosis causes selective alterations of peripheral-type benzodiazepine receptor expression in rat brain and peripheral tissues. Neurochem Int 35: 293–299.CrossRefGoogle Scholar
  30. Deutz NEP, Graaf AA, De Haan JG, De Bovée WMMJ, Chamuleau RAFM (1988) In vivo brain 1H-NMR spectroscopy (1-NMRS) during acute hepatic encephalopathy (HE). In: Soeters PB, Wilson JHP, Meijer AJ, Holm E, eds. Advances in ammonia metabolism and hepatic encephalopathy Excerpta Medica. Amsterdam: pp. 439–446.Google Scholar
  31. Fischbarg J, Kuang KY, Vera JC, Arant S, Silverstein SC, Loike J, Rosen OM (1990) Glucose transporters serve as water channels. Proc Natl Acad Sci USA 87: 3244–3247.PubMedCrossRefGoogle Scholar
  32. Ganz R, Swain M, Traber P, DalCanto M, Butterworth RF, Blei AT (1989) Ammonia-induced swelling of rat cerebral cortical slices: implications for the pathogenesis of brain edema in acute hepatic failure. Metab Brain Dis 4: 213–223.PubMedCrossRefGoogle Scholar
  33. Girard G, Giguère J-F, Butterworth RF (1993) Region-selective reductions in activities of glutamine synthetase in rat brain following portacaval anastomosis. Metab Brain Dis 8: 207–215.PubMedCrossRefGoogle Scholar
  34. Gregorios JB, Mozes LW, Norenberg L-OB, Norenberg MD (1985a) Morphologic effects of ammonia on primary astrocyte cultures. I. Light microscopic studies. J Neuropathol Exp Neurol 44: 397–403.CrossRefGoogle Scholar
  35. Gregorios JB, Mozes LW, Norenberg MD (1985b) Morphologic effects of ammonia on primary astrocyte cultures. II. Electron microscopic studies. J Neuropathol Exp Neurol 44: 404–414.CrossRefGoogle Scholar
  36. Hamberger A, Lindroth P, Nyström B (1982) Regulation of glutamate biosynthesis and release in vitro by low levels of ammonium ions. Brain Res 237: 339–350.PubMedCrossRefGoogle Scholar
  37. Hazell AS, Desjardins P, Butterworth RF (1999) Chronic exposure of rat primary astrocyte cultures to manganese results in increased binding sites for the “peripheral-type” benzodiazepine receptor ligand 3H-PK11195 Neurosci Lett 271: 5–8.PubMedCrossRefGoogle Scholar
  38. Hindfelt B, Plum F, Duffy TE (1977) Effects of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J Clin Invest 59: 386–396.PubMedCrossRefGoogle Scholar
  39. Itzhak Y, Norenberg MD (1994) Ammonia-induced upregulation of peripheral-type benzodiazepine receptors in cultured astrocytes labeled with [3H]-PK11195 Neurosci Lett 177: 35–38.PubMedCrossRefGoogle Scholar
  40. Itzhak Y, Roig-Cantisano A, Dombro RS, Norenberg MD (1995) Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain. Brain Res 705: 345–348.PubMedCrossRefGoogle Scholar
  41. Jalan R, Pollok A, Shah SH, Madhavan K, Simpson KJ (2002) Liver derived pro-inflammatory cytokines may be important in producing intracranial hypertension in ALF. J Hepatol 37: 536–538.PubMedCrossRefGoogle Scholar
  42. Jayakumar AR, Rao KV, Murthy CHR, Norenberg MD (2006) Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem Int 48: 623–628.PubMedGoogle Scholar
  43. Jiang W, Qu H, Desjardins P, Chatauret N, Bélanger M, Butterworth RF (2006) Unequivocal evidence for cytokine accumulation in brain in experimental acute liver failure. Hepatology 44 : (Suppl 1)366A.Google Scholar
  44. Kadota Y, Inoue K, Tokunaga R, Taketani S (1996) Induction of peripheral-type benzodiazepine receptors in mouse brain following thioacetamide-induced acute liver failure. Life Sci 58: 953–959.PubMedCrossRefGoogle Scholar
  45. Kato M, Hughes RD, Keays RT, Williams R (1992) Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 15: 1060–1066.PubMedCrossRefGoogle Scholar
  46. Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF (1997) Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with ALF. Neurosci Lett 229: 201–203.PubMedCrossRefGoogle Scholar
  47. Kosenko E, Kaminsky Y, Grau E, Minana MD, Grisolia S, Felipo V (1995) Nitroarginine, an inhibitor of nitric oxide synthetase, attenuates ammonia toxicity and ammonia-induced alterations in brain metabolism. Neurochem Res 20: 451–456.PubMedCrossRefGoogle Scholar
  48. Kril JJ, Butterworth RF (1996) Diencephalic and cerebellar pathology in alcoholic and non-alcoholic patients with end-stage liver disease. Hepatology 24: 1303.Google Scholar
  49. Lai JCK, Cooper AJL (1986) Brain α-ketoglutarate dehydrogenase: kinetic properties, regional distribution and effects of inhibitors. J Neurochem 47: 1376–1386.PubMedCrossRefGoogle Scholar
  50. Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A (2006) NMDA receptors mediate neuron-to-glia signalling in mouse cortical astrocytes. J Neurosci 26: 2673–2683.PubMedCrossRefGoogle Scholar
  51. Larsen FS, Gottstein J, Blei AT (2001) Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J Hepatol 34: 548–554.PubMedCrossRefGoogle Scholar
  52. Laubenberger J, Haussinger D, Boyer S, Guffer H, Henning J, Lange M (1997) Proton magnetic resonance spectroscopy of brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology 112: 1610–1616.PubMedCrossRefGoogle Scholar
  53. Lavoie J, Giguère JF, Pomier Layrargues G, Butterworth RF (1987) Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy. Metab Brain Dis 2: 283–290.PubMedCrossRefGoogle Scholar
  54. Lavoie J, Pomier-Layrargues G, Butterworth RF (1990) Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology 11: 874–878.PubMedCrossRefGoogle Scholar
  55. Leong DK, Therrien G, Swain MS, Butterworth RF (1994) Densities of binding sites of the “peripheral-type” benzodiazepine receptor ligand 3H-PK11195 are increased in brain 24 hours following portacaval anastomosis. Metab Brain Dis 9: 267–273.PubMedCrossRefGoogle Scholar
  56. Lockwood AH, Weissenborn K, Butterworth RF (1997) An image of the brain in patients with liver disease. Curr Opin Neurol 10: 525–533.PubMedCrossRefGoogle Scholar
  57. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283: 496–497.PubMedCrossRefGoogle Scholar
  58. Margulies JE, Thompson RC, Demetriou AA (1999) Aquaporin-4 water channel is up-regulated in the brain in fulminant hepatic failure. Hepatology 30: 395A.CrossRefGoogle Scholar
  59. Master S, Gottstein J, Blei AT (1999) Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 30: 876–880.PubMedCrossRefGoogle Scholar
  60. Mellon SH, Griffin LD (2002) Neurosteroids: biochemistry and clinical significance. Trends Endocrin Metab 13: 35–43.CrossRefGoogle Scholar
  61. Meyer HP, Legemate DA, Brom W, van den Rothuizen J (1998) Improvement of chronic hepatic encephalopathy in dogs by the benzodiazepine-receptor partial inverse agonist sarmazenil, but not by the antagonist flumazenil. Metab Brain Dis 13: 241–251.PubMedCrossRefGoogle Scholar
  62. Michalak A, Butterworth RF (1997) Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. Metab Brain Dis 12: 171–182.PubMedGoogle Scholar
  63. Mossakowski MJ, Renkawek K, Krasnicka Z, Smialek M, Pronaszko A (1970) Morphology and histochemistry of Wilsonian and hepatogenic gliopathy in tissue culture. Acta Neuropathol 16: 1–16.PubMedCrossRefGoogle Scholar
  64. Murthy CHRK, Rama Rao KV, Bai G, Norenberg MD (2001) Ammonia induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 66: 282–288.PubMedCrossRefGoogle Scholar
  65. Nagaki M, Iwai H, Naiki T, Ohnishi H, Muto Y, Moriwaki H (2000) High levels of serum interleukin-10 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis. J Infect Dis 182: 1103–1108.PubMedCrossRefGoogle Scholar
  66. Neary JT, Whittemore SR, Zhu Q, Norenberg MD (1994) Destabilization of glial fibrillary acidic protein mRNA in astrocytes by ammonia and protection by extracellular ATP. J Neurochem 63: 2021–2027.PubMedCrossRefGoogle Scholar
  67. Norenberg MD (1987) The role of astrocytes in hepatic encephalopathy. Neurochem Pathol 6: 13–33.PubMedCrossRefGoogle Scholar
  68. Norenberg MD (2003) Oxidative and nitrosative stress in ammonia neurotoxicity. Hepatology 37: 245–248.PubMedCrossRefGoogle Scholar
  69. Norenberg MD, Bender AS (1994) Astrocyte swelling in liver failure: role of glutamine and benzodiazepines. Acta Neurochir Suppl (Wien) 60: 24–27.Google Scholar
  70. Norenberg MD, Baker L, Norenberg LO, Blicharska J, Bruce-Gregorios JH, Neary JT (1991) Ammonia-induced astrocyte swelling in primary culture. Neurochem Res 16: 833–836.PubMedCrossRefGoogle Scholar
  71. Norenberg MD, Huo Z, Neary JT, Roig-Cantesano A (1997) The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 21: 124–133.PubMedCrossRefGoogle Scholar
  72. Pomier Layrargues G, Spahr L, Butterworth RF (1995) Increased manganese concentrations in pallidum of cirrhotic patients: cause of magnetic resonance hyperintensity? Lancet 345: 735.PubMedCrossRefGoogle Scholar
  73. Raghavendra Rao VL, Qureshi IA, Butterworth RF (1993) Increased densities of binding sites for the peripheral-type benzodiazepine receptor ligand [3H]-PK11195 in congenital ornithine transcarbamylase-deficient sparse fur mouse. Pediatr Res 34: 777–780.CrossRefGoogle Scholar
  74. Raghavendra Rao VL, Audet R, Therrien G, Butterworth RF (1994) Tissue-specific alterations of binding sites for peripheral-type benzodiazepine receptor ligand [3H]-PK11195 in rats following portacaval anastomosis. Dig Dis Sci 39: 1055–1063.CrossRefGoogle Scholar
  75. Raghavendra Rao VL, Audet RM, Butterworth RF (1997) Increased neuronal nitric oxide synthase expression in brain following portacaval anastomosis. Brain Res 765: 169–172.CrossRefGoogle Scholar
  76. Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R (2000) The systemic inflammatory response syndrome in acute liver failure. Hepatology 32:734–739.PubMedCrossRefGoogle Scholar
  77. Rose C (2006) Effect of ammonia on astrocytic glutamate uptake/release mechanisms. J Neurochem 97 (Suppl 1): 11–15.PubMedCrossRefGoogle Scholar
  78. Rose C, Kresse W, Kettenmann H (2005) Acute ammonia insult results in calcium-dependent glutamate release from cultured astrocytes: an effect of pH. J Biol Chem 280: 20937–20944.PubMedCrossRefGoogle Scholar
  79. Rothstein JD, McKhann G, Guarneri P, Barbaccia ML, Guidotti A, Costa E (1989) Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy. Ann Neurol 26: 57–62.PubMedCrossRefGoogle Scholar
  80. Sawara K, Desjardins P, Chatauret N, Bélanger M, Kato A, Suzuki K, Butterworth RF (2005) Selective effects of hypothermia on expression of oxidative stress markers in brains of rats with acute liver failure. Hepatology 42 : (Suppl 1)359A.Google Scholar
  81. Schipke CG, Ohlemeyer C, Matyash M, Nolte C, Kettenmann H, Kirchhoff F (2001) Astrocytes of the mouse neocortex express functional N-methyl-d-aspartate receptors. FASEB J 15: 1270–1272.PubMedGoogle Scholar
  82. Schliess F, Görg B, Fischer R, Desjardins P, Bidmon HJ, Herrmann A, Butterworth RF, Zilles K, Häussinger D (2002) Ammonia induces MK-801 sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J 16: 739–741.PubMedGoogle Scholar
  83. Shiraishi T, Black KL, Ikezaki K, Becker DP (1991) Peripheral benzodiazepine induces morphological changes and proliferation of mitochondria in glioma cells. J Neurosci Res 30: 463–474.PubMedCrossRefGoogle Scholar
  84. Sobel RA, Armond SJ, De Forno LS, Eng LF (1981) Glial fibrillary acidic protein in hepatic encephalopathy: An immunohistochemical study. J Neuropathol Exp Neurol 40: 625–632.PubMedCrossRefGoogle Scholar
  85. Sonnewald U, Therrien G, Butterworth RF (1996) Portal-systemic encephalopathy, disorder of neuron-astrocytic metabolic trafficking: evidence from 13C-NMR studies. J Neurochem 67: 1711–1717.PubMedCrossRefGoogle Scholar
  86. Staub F, Baethmann A, Peters J, Weight H, Keupski O (1990) Effects of lactacidosis on glial cell volume and viability. J Cereb Blood Flow and Metab 10: 866–876.CrossRefGoogle Scholar
  87. Suarez I, Bodega G, Fernandez B (2000) Modulation of glutamate transporters (GLAST, GLT-1 and EAAC1) in the rat cerebellum following portacaval anastomosis. Brain Res 859: 293–302.PubMedCrossRefGoogle Scholar
  88. Swain MS, Bergeron M, Audet R, Blei AT, Butterworth RF (1992) Monitoring of neurotransmitter amino acids by means of an indwelling cisterna magna catheter. A comparison of two rodent models of fulminant hepatic failure. Hepatology 16: 1028–1035.PubMedCrossRefGoogle Scholar
  89. Szerb JC, Butterworth RF (1992) Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol 39: 135–153.PubMedCrossRefGoogle Scholar
  90. Tanigami H, Rebel A, Martin LJ, Chen TY, Brusilow SW, Traystman RJ, Koehler RC (2005) Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats. Neuroscience 131: 437–449.PubMedCrossRefGoogle Scholar
  91. Therrien G, Giguère JF, Butterworth RF (1991) Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy. Metab Brain Dis 6: 225–231.PubMedCrossRefGoogle Scholar
  92. Ukida M, Morishita H, Morimoto Y, Usui H, Nagashima H (1988) Limited glutamine synthesis in brains of dog with portacaval anastomosis after 15N-ammonium chloride loading. In: Soeters PB, Wilson JHP, Meijer AJ, Holm E, eds. Advances in ammonia metabolism and hepatic encephalopathy Excerpta Medica. Amsterdam: pp. 433–438.Google Scholar
  93. Vaquero J, Chung C, Blei AT (2003) Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy. Ann Hepatol 2: 12–22.PubMedGoogle Scholar
  94. Vaquero J, Rose C, Butterworth RF (2005) Keeping cool in acute liver failure: rationale for the use of mild hypothermia. J Hepatol 43: 1067–1077.PubMedCrossRefGoogle Scholar
  95. Vogels BA, Maas MA, Daalhuisen J, Quack G, Chamuleau RA (1997) Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 25: 820–827.PubMedCrossRefGoogle Scholar
  96. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6: 626–640.PubMedCrossRefGoogle Scholar
  97. Willard-Mack CL, Koehler RC, Hirata T, Cork LC, Takahashi H, Traystman RJ, Brusilow SW (1996) Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 71: 589–599.PubMedCrossRefGoogle Scholar
  98. Zwingmann C, Desjardins P, Chatauret N, Michalak A, Hazell AS, Butterworth RF (2002) Reduced astrocytic glycine transporter Glyt-1 in acute liver failure. Metab Brain Dis 17: 263–274.PubMedCrossRefGoogle Scholar
  99. Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [1H-13C] nuclear magnetic resonance study. Hepatology 37: 420–428.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Neuroscience Research Unit, CHUMUniversity of MontrealMontrealCanada

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