Metabolic Brain Disease

, 24:119 | Cite as

RNA oxidation and zinc in hepatic encephalopathy and hyperammonemia

  • Freimut Schliess
  • Boris Görg
  • Dieter Häussinger
Original Paper

Abstract

Hepatic encephalopathy is a neuropsychiatric manifestation of acute and chronic liver failure. Ammonia plays a key role in the pathogenesis of hepatic encephalopathy by inducing astrocyte swelling and/or sensitizing astrocytes to swelling by a heterogeneous panel of precipitating factors and conditions. Whereas astrocyte swelling in acute liver failure contributes to a clinically overt brain edema, a low grade glial edema without clinically overt brain edema is observed in hepatic encephalopathy in liver cirrhosis. Astrocyte swelling produces reactive oxygen and nitrogen oxide species (ROS/RNOS), which again increase astrocyte swelling, thereby creating a self-amplifying signaling loop. Astroglial swelling and ROS/RNOS increase protein tyrosine nitration and may account for neurotoxic effects of ammonia and other precipitants of hepatic encephalopathy. Recently, RNA oxidation and an increase of free intracellular zinc ([Zn2+]i) were identified as further consequences of astrocyte swelling and ROS/RNOS production. An elevation of [Zn2+]i mediates mRNA expression of metallothionein and the peripheral benzodiazepine receptor (PBR) induced by hypoosmotic astrocyte swelling. Further, Zn2+ mediates RNA oxidation in ammonia-treated astrocytes. In the brain of hyperammonemic rats oxidized RNA localizes in part to perivascular astrocyte processes and to postsynaptic dendritic spines. RNA oxidation may impair postsynaptic protein synthesis, which is critically involved in learning and memory consolidation. RNA oxidation offers a novel explanation for multiple disturbances of neurotransmitter systems and gene expression and the cognitive deficits observed in hepatic encephalopathy.

Keywords

Astrocytes Cell volume Oxidative stress Ammonia Brain Peripheral benzodiazepine receptor Metallothionein 

References

  1. Arslan P, Di VF, Beltrame M, Tsien RY, Pozzan T (1985) Cytosolic Ca2+ homeostasis in Ehrlich and Yoshida carcinomas. A new, membrane-permeant chelator of heavy metals reveals that these ascites tumor cell lines have normal cytosolic free Ca2+. J Biol Chem 260:2719–2727PubMedGoogle Scholar
  2. Aschner M (1996) The functional significance of brain metallothioneins. FASEB J 10:1129–1136PubMedGoogle Scholar
  3. Aschner M, Conklin DR, Yao CP, Allen JW, Tan KH (1998) Induction of astrocyte metallothioneins (MTs) by zinc confers resistance against the acute cytotoxic effects of methylmercury on cell swelling, Na+ uptake, and K+ release. Brain Res 813:254–261PubMedGoogle Scholar
  4. Bender AS, Norenberg MD (1998) Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes. J Neurosci Res 54:673–680PubMedGoogle Scholar
  5. Bender AS, Rivera IV, Norenberg MD (1992) Tumor necrosis factor alpha induces astrocyte swelling. Trans Am Soc Neurochem 23:113Google Scholar
  6. Bender AS, Schousboe A, Reichelt W, Norenberg MD (1998) Ionic mechanisms in glutamate-induced astrocyte swelling: role of K+ influx. J Neurosci Res 52:307–321PubMedGoogle Scholar
  7. Beyersmann D, Haase H (2001) Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 14:331–341PubMedGoogle Scholar
  8. Bezzi P, Domercq M, Vesce S, Volterra A (2001) Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications. Prog Brain Res 132:255–265PubMedGoogle Scholar
  9. Bishop GM, Dringen R, Robinson SR (2007) Zinc stimulates the production of toxic reactive oxygen species (ROS) and inhibits glutathione reductase in astrocytes. Free Radic Biol Med 42:1222–1230PubMedGoogle Scholar
  10. Blei AT, Olafsson S, Therrien G, Butterworth RF (1994) Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology 19:1437–1444PubMedCrossRefGoogle Scholar
  11. Brusilow SW (1986) Hepatic encephalopathy. New Engl J Med 314:786–787PubMedGoogle Scholar
  12. Brusilow SW (2002) Hyperammonemic encephalopathy. Medicine (Baltimore) 81:240–249Google Scholar
  13. Butterworth RF (2000) The astrocytic (“peripheral-type”) benzodiazepine receptor: role in the pathogenesis of portal-systemic encephalopathy. Neurochem Int 36:411–416PubMedGoogle Scholar
  14. Butterworth RF (2003) Molecular neurobiology of acute liver failure. Semin Liver Dis 23:251–258PubMedGoogle Scholar
  15. Chepkova AN, Sergeeva OA, Haas HL (2006) Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis 23:512–521PubMedGoogle Scholar
  16. Chetri K, Choudhuri G (2003) Role of trace elements in hepatic encephalopathy: zinc and manganese. Indian J Gastroenterol 22(Suppl 2):S28–S30PubMedGoogle Scholar
  17. Cordoba J, Gottstein J, Blei AT (1996) Glutamine, myo-inositol and organic brain osmolytes after portacaval anastomosis in the rat—implications for ammonia-induced brain edema. Hepatology 24:919–923PubMedGoogle Scholar
  18. Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L, Vargas V, Margarit C, Kulisewsky J, Esteban R, Guardia J (2001) The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation. J Hepatol 35:598–604PubMedGoogle Scholar
  19. Ding Q, Dimayuga E, Markesbery WR, Keller JN (2004) Proteasome inhibition increases DNA and RNA oxidation in astrocyte and neuron cultures. J Neurochem 91:1211–1218PubMedGoogle Scholar
  20. Ding Q, Markesbery WR, Chen Q, Li F, Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer’s disease. J Neurosci 25:9171–9175PubMedGoogle Scholar
  21. Dombro RS, Bender AS, Norenberg MD (2000) Association between cell swelling and glycogen content in cultured astrocytes. Int J Dev Neurosci 18:161–169PubMedGoogle Scholar
  22. Eisenberg D, Gill HS, Pfluegl GM, Rotstein SH (2000) Structure-function relationships of glutamine synthetases. Biochim Biophys Acta 1477:122–145PubMedGoogle Scholar
  23. Erceg S, Monfort P, Hernandez-Viadel M, Llansola M, Montoliu C, Felipo V (2005) Restoration of learning ability in hyperammonemic rats by increasing extracellular cGMP in brain. Brain Res 1036:115–121PubMedGoogle Scholar
  24. Frazzini V, Rockabrand E, Mocchegiani E, Sensi SL (2006) Oxidative stress and brain aging: is zinc the link? Biogerontology 7:307–314PubMedGoogle Scholar
  25. Giatzakis C, Papadopoulos V (2004) Differential utilization of the promoter of peripheral-type benzodiazepine receptor by steroidogenic versus nonsteroidogenic cell lines and the role of Sp1 and Sp3 in the regulation of basal activity. Endocrinology 145:1113–1123PubMedGoogle Scholar
  26. Giguere JF, Hamel E, Butterworth RF (1992) Increased densities of binding sites for the ‘peripheral-type’ benzodiazepine receptor ligand [3H]PK 11195 in rat brain following portacaval anastomosis. Brain Res 585:295–298PubMedGoogle Scholar
  27. Görg B, Foster N, Reinehr RM, Bidmon HJ, Höngen A, Häussinger D, Schliess F (2003) Benzodiazepine-induced protein tyrosine nitration in rat astrocytes. Hepatology 37:334–342PubMedGoogle Scholar
  28. Görg B, Bidmon HJ, Keitel V, Foster N, Goerlich R, Schliess F, Häussinger D (2006) Inflammatory cytokines induce protein tyrosine nitration in rat astrocytes. Arch Biochem Biophys 449:104–114PubMedGoogle Scholar
  29. Görg B, Qvartskhava N, Keitel V, Bidmon HJ, Selbach O, Schliess F, Häussinger D (2008) Ammonia increases RNA oxidation in cultured astrocytes and brain in vivo. Hepatology 48:567–579PubMedGoogle Scholar
  30. Hansson E, Rönnbäck L (1995) Astrocytes in glutamate neurotransmission. FASEB Journal 9:343–350PubMedGoogle Scholar
  31. Häussinger D (1996) The role of cellular hydration in the regulation of cell function. Biochem J 313:697–710PubMedGoogle Scholar
  32. Häussinger D (2006) Low grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 43:1187–1190PubMedGoogle Scholar
  33. Häussinger D, Lang F (1992) Cell volume and hormone action. Trends Pharmacol Sci 13:371–373PubMedGoogle Scholar
  34. Häussinger D, Schliess F (2005a) Astocyte swelling and oxidative stress in hepatic encephalopathy. Neurochem Int 47:64–70PubMedGoogle Scholar
  35. Häussinger D, Schliess F (2008) Pathogenetic mechanisms of hepatic encephalopathy. Gut 57:1156–1165PubMedGoogle Scholar
  36. Häussinger D, Laubenberger J, vom Dahl S, Ernst T, Bayer S, Langer M, Gerok W, Hennig J (1994) Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 107:1475–1480PubMedGoogle Scholar
  37. Häussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S (2000) Hepatic encephalopathy in chronic liver desease: a clinical manifestation of astrocyte swelling and low grade cerebral edema. J Hepatol 32:1035–1038PubMedGoogle Scholar
  38. Hazell AS, Butterworth RF (1999) Hepatic encephalopathy: an update of pathophysiologic mechanisms. Proc Soc Exp Biol Med 222:99–112PubMedGoogle Scholar
  39. Hermenegildo C, Marcaida G, Montoliu C, Grisolia S, Minana MD, Felipo V (1996) NMDA receptor antagonists prevent acute ammonia toxicity in mice. Neurochem Res 21:1237–1244PubMedGoogle Scholar
  40. Hermenegildo C, Monfort P, Felipo V (2000) Activation of N-methyl-D-aspartate receptors in rat brain in vivo following acute ammonia intoxication: characterization by in vivo brain microdialysis. Hepatology 31:709–715PubMedGoogle Scholar
  41. Hu HL, Chen RD (1992) Changes in free radicals, trace elements, and neurophysiological function in rats with liver damage induced by D-galactosamine. Biol Trace Elem Res 34:19–25PubMedGoogle Scholar
  42. Itzhak Y, Norenberg MD (1994) Ammonia-induced upregulation of peripheral-type benzodiazepine receptors in cultured astrocytes labeled with [3H]PK 11195. Neurosci Lett 177:35–38PubMedGoogle Scholar
  43. Itzhak Y, Bender AS, Norenberg MD (1994) Effect of hypoosmotic stress on peripheral-type benzodiazepine receptors in cultured astrocytes. Brain Res 644:221–225PubMedGoogle Scholar
  44. Jackson SH, Miller GF, Segal BH, Mardiney M, Domachowske JB, Gallin JI, Holland SM (2001) IFN-gamma is effective in reducing infections in the mouse model of chronic granulomatous disease (CGD). J Interferon Cytokine Res 21:567–573PubMedGoogle Scholar
  45. Jayakumar AR, Rao KV, Murthy C, Norenberg MD (2006) Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem Int 48:623–628PubMedGoogle Scholar
  46. Kale RA, Gupta RK, Saraswat VA, Hasan KM, Trivedi R, Mishra AM, Ranjan P, Pandey CM, Narayana PA (2006) Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Hepatology 43:698–706PubMedGoogle Scholar
  47. Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–1038PubMedGoogle Scholar
  48. Kasai H, Chung MH, Jones DS, Inoue H, Ishikawa H, Kamiya H, Ohtsuka E, Nishimura S (1991) 8-Hydroxyguanine, a DNA adduct formed by oxygen radicals: its implication on oxygen radical-involved mutagenesis/carcinogenesis. J Toxicol Sci 16:95–105PubMedGoogle Scholar
  49. Kimelberg HK (1995) Currend concepts of brain edema—review of laboratory investigations. J Neurosurg 83:1051–1059PubMedGoogle Scholar
  50. Kosenko E, Kaminski Y, Lopata O, Muravyov N, Felipo V (1999) Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radic Biol Med 26:1369–1374PubMedGoogle Scholar
  51. Kosenko E, Montoliu C, Giordano G, Kaminsky Y, Venediktova N, Buryanov Y, Felipo V (2004) Acute ammonia intoxication induces an NMDA receptor-mediated increase in poly(ADP-ribose) polymerase level and NAD metabolism in nuclei of rat brain cells. J Neurochem 89:1101–1110PubMedGoogle Scholar
  52. Krezel A, Hao Q, Maret W (2007) The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch Biochem Biophys 463:188–200PubMedGoogle Scholar
  53. Kröncke KD (2001) Cysteine-Zn2+ complexes: unique molecular switches for inducible nitric oxide synthase-derived NO. FASEB J 15:2503–2507PubMedGoogle Scholar
  54. Kröncke KD (2007) Cellular stress and intracellular zinc dyshomeostasis. Arch Biochem Biophys 463:183–187PubMedGoogle Scholar
  55. Kruczek C, Görg B, Keitel V, Pirev E, Kröncke KD, Schliess F, Häussinger D (2008) Hypoosmotic swelling affects zinc homeostasis in cultured rat astrocytes. GLIA 57:79–92Google Scholar
  56. Laity JH, Andrews GK (2007) Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1). Arch Biochem Biophys 463:201–210PubMedGoogle Scholar
  57. Larsen FS, Gottstein J, Blei AT (2001) Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J Hepatol 34:548–554PubMedGoogle Scholar
  58. Li Y, Hough CJ, Suh SW, Sarvey JM, Frederickson CJ (2001) Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J Neurophysiol 86:2597–2604PubMedGoogle Scholar
  59. Loomba V, Pawar G, Dhar KL, Setia MS (1995) Serum zinc levels in hepatic encephalopathy. Indian J Gastroenterol 14:51–53PubMedGoogle Scholar
  60. Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M (1996) Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology 23:1084–1092PubMedGoogle Scholar
  61. Martinez HA, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195:1356–1358Google Scholar
  62. Master S, Gottstein J, Blei AT (1999) Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 30:876–880PubMedGoogle Scholar
  63. Miese F, Kircheis G, Wittsack HJ, Wenserski F, Hemker J, Modder U, Häussinger D, Cohnen M (2006) 1H-MR spectroscopy, magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy. AJNR Am J Neuroradiol 27:1019–1026PubMedGoogle Scholar
  64. Minguez B, Garcia-Pagan JC, Bosch J, Turnes J, Alonso J, Rovira A, Cordoba J (2006) Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy. Hepatology 43:707–714PubMedGoogle Scholar
  65. Morgan MY (1998) Cerebral magnetic resonance imaging in patients with chronic liver disease. Metab Brain Dis 13:273–290PubMedGoogle Scholar
  66. Murthy CR, Rama-Rao KV, Bai G, Norenberg MD (2001) Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 66:282–288PubMedGoogle Scholar
  67. Musavi S, Kakkar P (1998) Diazepam induced early oxidative changes at the subcellular level in rat brain. Mol Cell Biochem 178:41–46PubMedGoogle Scholar
  68. Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111PubMedGoogle Scholar
  69. Norenberg MD (1994) Astrocyte responses to CNS injury. J Neuropathol Exp Neurol 53:213–220PubMedGoogle Scholar
  70. Norenberg MD (1996) Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 16:245–253PubMedGoogle Scholar
  71. Norenberg MD (2003) Oxidative and nitrosative stress in ammonia neurotoxicity. Hepatology 37:245–248PubMedGoogle Scholar
  72. Norenberg MD, Baker L, Norenberg LO, Blicharska J, Bruce-Gregorios JH, Neary JT (1991) Ammonia-induced astrocyte swelling in primary culture. Neurochem Res 16:833–836PubMedGoogle Scholar
  73. Norenberg MD, Jayakumar AR, Rama-Rao KV (2004) Oxidative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 19:313–329PubMedGoogle Scholar
  74. Nunomura A, Honda K, Takeda A, Hirai K, Zhu X, Smith MA, Perry G (2006) Oxidative damage to RNA in neurodegenerative diseases. J Biomed Biotechnol 2006:1–6Google Scholar
  75. Panickar KS, Jayakumar AR, Rama Rao KV, Norenberg MD (2007) Downregulation of the 18-kDa translocator protein: Effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes. GLIA 55:1720–1727PubMedGoogle Scholar
  76. Pickering M, Cumiskey D, O’Connor JJ (2005) Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol 90:663–670PubMedGoogle Scholar
  77. Possel H, Noack H, Putzke J, Wolf G, Sies H (2000) Selective upregulation of inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS) and cytokines in microglia: in vitro and in vivo studies. GLIA 32:51–59PubMedGoogle Scholar
  78. Rahelic D, Kujundzic M, Romic Z, Brkic K, Petrovecki M (2006) Serum concentration of zinc, copper, manganese and magnesium in patients with liver cirrhosis. Coll Antropol 30:523–528PubMedGoogle Scholar
  79. Rama-Rao KV, Jayakumar AR, Norenberg DM (2003a) Ammonia neurotoxicity: role of the mitochondrial permeability transition. Metab Brain Dis 18:113–127PubMedGoogle Scholar
  80. Rama-Rao KV, Jayakumar AR, Norenberg MD (2003b) Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine. Neurochem Int 43:517–523PubMedGoogle Scholar
  81. Reding P, Duchateau J, Bataille C (1984) Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial. Lancet 2:493–495PubMedGoogle Scholar
  82. Reinehr R, Görg B, Becker S, Qvartskhava N, Bidmon HJ, Selbach O, Haas HL, Schliess F, Häussinger D (2007) Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices. GLIA 55:758–771PubMedGoogle Scholar
  83. Ross BD, Jacobson S, Villamil F, Korula J, Kreis R, Ernst T, Shonk T, Moats RA (1994) Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities. Radiology 193:457–463PubMedGoogle Scholar
  84. Saffari Y, Sadrzadeh SM (2004) Green tea metabolite EGCG protects membranes against oxidative damage in vitro. Life Sci 74:1513–1518PubMedGoogle Scholar
  85. Schliess F, Häussinger D (2005) The cellular hydration state: role in apoptosis and proliferation. Signal Transduct 6:297–302Google Scholar
  86. 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 16:739–741PubMedGoogle Scholar
  87. Schliess F, Foster N, Görg B, Reinehr R, Häussinger D (2004) Astrocyte swelling increases protein tyrosine nitration in cultured rat astrocytes. GLIA 47:21–29PubMedGoogle Scholar
  88. Schliess F, Görg B, Häussinger D (2006a) Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm. Biol Chem 387:1363–1370PubMedGoogle Scholar
  89. Schliess F, Görg B, Reinehr RM, Bidmon HJ, Häussinger D (2006b) Osmotic and oxidative stress in hepatic encephalopathy. In: Häussinger D, Kircheis G, Schliess F (eds) Hepatic encephalopathy and nitrogen metabolism. Springer, Dordrecht, The Netherlands, pp 20–42Google Scholar
  90. Schliess F, Reinehr R, Häussinger D (2007) Osmosensing and signaling in the regulation of mammalian cell function. FEBS J 274:5799–5803PubMedGoogle Scholar
  91. Schuman EM, Dynes JL, Steward O (2006) Synaptic regulation of translation of dendritic mRNAs. J Neurosci 26:7143–7146PubMedGoogle Scholar
  92. Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR, Kaczmarek LK, Weiss JH (2003) Modulation of mitochondrial function by endogenous Zn2+ pools. Proc Natl Acad Sci U S A 100:6157–6162PubMedGoogle Scholar
  93. Sergeeva OA, Schulz D, Doreulee N, Ponomarenko AA, Selbach O, Borsch E, Kircheis G, Huston JP, Häussinger D, Haas HL (2005) Deficits in cortico-striatal synaptic plasticity and behavioral habituation in rats with portacaval anastomosis. Neuroscience 134:1091–1098PubMedGoogle Scholar
  94. Shah NJ, Neeb H, Zaitsev M, Steinhoff S, Kircheis G, Amunts K, Häussinger D, Zilles K (2003) Quantitative T1 mapping of hepatic encephalopathy using magnetic resonance imaging. Hepatology 38:1219–1226PubMedGoogle Scholar
  95. Shah NJ, Neeb H, Kircheis G, Engels P, Häussinger D, Zilles K (2008) Quantitative cerebral water content mapping in hepatic encephalopathy. Neuroimage 43:706–717Google Scholar
  96. Shan X, Lin CL (2006) Quantification of oxidized RNAs in Alzheimer’s disease. Neurobiol Aging 27:657–662PubMedGoogle Scholar
  97. Shan X, Tashiro H, Lin CL (2003) The identification and characterization of oxidized RNAs in Alzheimer’s disease. J Neurosci 23:4913–4921PubMedGoogle Scholar
  98. Shan X, Chang Y, Lin CL (2007) Messenger RNA oxidation is an early event preceding cell death and causes reduced protein expression. FASEB J 21:2753–2764PubMedGoogle Scholar
  99. Shawcross DL, Balata S, Olde-Damink SW, Hayes PC, Wardlaw J, Marshall I, Deutz NE, Williams R, Jalan R (2004) Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia. Am J Physiol Gastrointest Liver Physiol 287:G503–G509PubMedGoogle Scholar
  100. Sykova E, Vargova L, Prokopova S, Simonova Z (1999) Glial swelling and astrogliosis produce diffusion barriers in the rat spinal cord. GLIA 25:56–70PubMedGoogle Scholar
  101. Takahashi H, Koehler RC, Brusilow SW, Traystman RJ (1991) Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 261:H825–H829PubMedGoogle Scholar
  102. Takeda A (2001) Zinc homeostasis and functions of zinc in the brain. Biometals 14:343–351PubMedGoogle Scholar
  103. 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 131:437–449PubMedGoogle Scholar
  104. Timmermann L, Gross J, Kircheis G, Häussinger D, Schnitzler A (2002) Cortical origin of mini-asterixis in hepatic encephalopathy. Neurology 58:295–298PubMedGoogle Scholar
  105. Timmermann L, Gross J, Butz M, Kircheis G, Häussinger D, Schnitzler A (2003) Mini-asterixis in hepatic encephalopathy induced by pathologic thalamo-motor-cortical coupling. Neurology 61:689–692PubMedGoogle Scholar
  106. Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118PubMedGoogle Scholar
  107. Vallee BL, Wacker WE, Bartholomay AF, Hoch FL (1957) Zinc metabolism in hepatic dysfunction. II. Correlation of metabolic patterns with biochemical findings. N Engl J Med 257:1055–1065PubMedGoogle Scholar
  108. van der Rijt CC, Schalm SW, Schat H, Foeken K, De JG (1991) Overt hepatic encephalopathy precipitated by zinc deficiency. Gastroenterology 100:1114–1118PubMedGoogle Scholar
  109. Vaquero J, Chung C, Cahill ME, Blei AT (2003) Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis 23:259–269PubMedGoogle Scholar
  110. 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 71:589–599PubMedGoogle Scholar
  111. Yang SS, Lai YC, Chiang TR, Chen DF, Chen DS (2004) Role of zinc in subclinical hepatic encephalopathy: comparison with somatosensory-evoked potentials. J Gastroenterol Hepatol 19:375–379PubMedGoogle Scholar
  112. Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, Tsuji T (2001) Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama 55:349–355PubMedGoogle Scholar
  113. Zeneroli ML (1985) Hepatic encephalopathy. experimental studies in a rat model of fulminant hepatic failure. J Hepatol 1:301–311PubMedGoogle Scholar
  114. Zeneroli ML, Baraldi M (1990) Neurotransmission in hepatic encephalopathy. Adv Exp Med Biol 272:135–148PubMedGoogle Scholar
  115. Zielinska M, Law RO, Albrecht J (2003) Excitotoxic mechanism of cell swelling in rat cerebral cortical slices treated acutely with ammonia. Neurochem Int 43:299–303PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Freimut Schliess
    • 1
    • 2
  • Boris Görg
    • 1
  • Dieter Häussinger
    • 1
  1. 1.Heinrich-Heine-Universität Düsseldorf, Klinik für GastroenterologieHepatologie, und InfektiologieDüsseldorfGermany
  2. 2.Profil Institut für Stoffwechselforschung GmbHNeussGermany

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