Brain edema in acute liver failure: mechanisms and concepts

Metabolic Brain Disease

Volumn 29, Issue 4, 2014, Pages 927-936

  Rama Rao, Kakulavarapu V ^a   Jayakumar, Arumugam R ^a,b   Norenberg, Michael D ^a,b  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Acute liver failure; Ammonia; Aquaporin 4; Astrocytes; Brain edema; Endothelial cells; Hepatic encephalopathy; Inflammation; Ion transporters; Microglia; Oxidative nitrative stress; Vasogenic edema

Indexed keywords

AMMONIA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; NERVE PROTEIN;

ACUTE DISEASE; ANIMAL; ASTROCYTE; BODY WATER; BRAIN EDEMA; CELL SIZE; CHEMICALLY INDUCED; COMPLICATION; EPIDEMIOLOGY; HOMEOSTASIS; HUMAN; INFECTION; INFLAMMATION; INTRACRANIAL HYPERTENSION; ION TRANSPORT; LIVER FAILURE; METABOLISM; METHODOLOGY; NITROSATION; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PHYSIOLOGY; ULTRASTRUCTURE;

ACUTE DISEASE; AMMONIA; ANIMALS; ASTROCYTES; BODY WATER; BRAIN EDEMA; CELL SIZE; CONFOUNDING FACTORS (EPIDEMIOLOGY); HOMEOSTASIS; HUMANS; INFECTION; INFLAMMATION; INTRACRANIAL HYPERTENSION; ION TRANSPORT; LIVER FAILURE; MITOGEN-ACTIVATED PROTEIN KINASES; NERVE TISSUE PROTEINS; NF-KAPPA B; NITROSATION; OXIDATIVE STRESS; RESEARCH DESIGN;

EID: 84911805350     PISSN: 08857490     EISSN: 15737365     Source Type: Journal    
DOI: 10.1007/s11011-014-9502-y     Document Type: Article

References (116)

1. Alvarez VM, Rama Rao KV, Brahmbhatt M, Norenberg MD (2011) Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. J Neurosci Res 89:2028–2040
2. Back A, Tupper KY, Bai T, Chiranand P, Goldenberg FD, Frank JI, Brorson JR (2011) Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model. Neurol Res 33:1100–1108
3. Bai G, Rama Rao KV, Murthy CR, Panickar KS, Jayakumar AR, Norenberg MD (2001) Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J Neurosci Res 66:981–991
4. Bernal W, Auzinger G, Dhawan A, Wendon J (2010) Acute liver failure. Lancet 376:190–201
5. Bismuth A, Arulnaden JL, Debat P, Farrokhi P, Farahmand H, Saliba F, Samuel D, Decorps Declere A, Gillet MC, Serre C et al (1988) Liver transplantation and transfusion. Rev Fr Transfus Immunohematol 31:603–630
6. Blei AT (1991) Cerebral edema and intracranial hypertension in acute liver failure: distinct aspects of the same problem. Hepatology 13:376–379
7. 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
8. Bodega G, Suarez I, Paniagua C, Vacas E, Fernandez B (2007) Effect of ammonia, glutamine, and serum on calcineurin, p38MAPK-diP, GADD153/CHOP10, and CNTF in primary rat astrocyte cultures. Brain Res 1175:126–133
9. Bodega G, Suarez I, Lopez-Fernandez LA, Garcia MI, Kober M, Penedo M, Luna M, Juarez S, Ciordia S, Oria M, Cordoba J, Fernandez B (2012) Ammonia induces aquaporin-4 rearrangement in the plasma membrane of cultured astrocytes. Neurochem Int 61:1314–1324
10. Brahma B, Forman RE, Stewart EE, Nicholson C, Rice ME (2000) Ascorbate inhibits edema in brain slices. J Neurochem 74:1263–1270
11. Broekemeier KM, Dempsey ME, Pfeiffer DR (1989) Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J Biol Chem 264:7826–7830
12. Bruck J, Görg B, Bidmon HJ, Zemtsova I, Qvartskhava N, Keitel V, Kircheis G, Häussinger D (2011) Locomotor impairment and cerebrocortical oxidative stress in portal vein ligated rats in vivo. J Hepatol 54:251–257
13. Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010) Toll-like receptor 4 in CNS pathologies. J Neurochem 114:13–27
14. Butterworth RF (2013) The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol 10:522–528
15. Cauli O, Lopez-Larrubia P, Rodrigo R, Agusti A, Boix J, Nieto-Charques L, Cerdan S, Felipo V (2011) Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats. Gastroenterology 140:638–645
16. Cauli O, Gonzalez-Usano A, Cabrera-Pastor A, Gimenez-Garzo C, Lopez-Larrubia P, Ruiz-Sauri A, Hernandez-Rabaza V, Duszczyk M et al (2013) Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain. Neuromol Med doi:10.1007/s12017-013-8283-5
17. Chan PH, Yurko M, Fishman RA (1982) Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices. J Neurochem 38:525–531
18. Chavarria L, Alonso J, Rovira A, Cordoba J (2011) Neuroimaging in acute liver failure. Neurochem Int 59:1175–1180
19. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653
20. del Zoppo GJ (2009) Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neuroscience 158:972–982
21. Detry O, De Roover A, Honore P, Meurisse M (2006) Brain edema and intracranial hypertension in fulminant hepatic failure: pathophysiology and management. World J Gastroenterol 12:7405–7412
22. Ede RJ, Williams RW (1986) Hepatic encephalopathy and cerebral edema. Semin Liver Dis 6:107–118
23. Eefsen M, Jelnes P, Schmidt LE, Vainer B, Bisgaard HC, Larsen FS (2010) Brain expression of the water channels aquaporin-1 and −4 in mice with acute liver injury, hyperammonemia and brain edema. Metab Brain Dis 25:315–323
24. +-induced taurine release from cultured rabbit Muller cells: role of Na+ and Cl- ions and relation to cell volume changes. Glia 10:114–120
25. 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
26. Garcovich M, Zocco MA, Roccarina D, Ponziani FR, Gasbarrini A (2012) Prevention and treatment of hepatic encephalopathy: focusing on gut microbiota. World J Gastroenterol 18:6693–6700
27. Görg B, Qvartskhava N, Keitel V, Bidmon HJ, Selbach O, Schliess F, Häussinger D (2008) Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo. Hepatology 48:567–579
28. Görg B, Qvartskhava N, Bidmon HJ, Palomero-Gallagher N, Kircheis G, Zilles K, Häussinger D (2010) Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy. Hepatology 52:256–265
29. Görg B, Bidmon HJ, Häussinger D (2013) Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy. Hepatology 57:2436–2447
30. Häussinger D, Görg B (2010) Interaction of oxidative stress, astrocyte swelling and cerebral ammonia toxicity. Curr Opin Clin Nutr Metab Care 13:87–92
31. Hoffmann EK (1992) Cell swelling and volume regulation. Can J Physiol Pharmacol 70(Suppl):S310–S313
32. Hoffmann EK, Lambert IH, Pedersen SF (2009) Physiology of cell volume regulation in vertebrates. Physiol Rev 89:193–277
33. Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N (1995) Fulminant hepatic failure: summary of a workshop. Hepatology 21:240–252
34. Isenring P, Forbush B (2001) Ion transport and ligand binding by the Na-K-Cl cotransporter, structure-function studies. Comp Biochem Physiol A Mol Integr Physiol 130:487–497
35. Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A (2004) Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol 41:613–620
36. Jayakumar AR, Panickar KS, Murthy Ch R, Norenberg MD (2006) Oxidative stress and mitogen-activated protein kinase phosphorylation mediate ammonia-induced cell swelling and glutamate uptake inhibition in cultured astrocytes. J Neurosci 26:4774–4784
37. Jayakumar AR, Liu M, Moriyama M, Ramakrishnan R, Forbush B 3rd, Reddy PV, Norenberg MD (2008) Na-K-Cl cotransporter-1 in the mechanism of ammonia-induced astrocyte swelling. J Biol Chem 283:33874–33882
38. Jayakumar AR, Bethea JR, Tong XY, Gomez J, Norenberg MD (2011) NF-kappaB in the mechanism of brain edema in acute liver failure: studies in transgenic mice. Neurobiol Dis 41:498–507
39. Jayakumar AR, Tong XY, Ospel J, Norenberg MD (2012) Role of cerebral endothelial cells in the astrocyte swelling and brain edema associated with acute hepatic encephalopathy. Neuroscience 218:305–316
40. Jayakumar AR, Ruiz-Cordero R, Tong XY, Norenberg MD (2013a) Brain edema in acute liver failure: role of neurosteroids. Arch Biochem Biophys 536:171–175
41. Jayakumar AR, Tong XY, Curtis KM, Ruiz-Cordero R, Abreu MT, Norenberg MD (2013b) Increased toll-like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy. J Neurochem. doi:10.1111/jnc.12516
42. Jayakumar AR, Valdes V, Tong XY, Shamaladevi N, Gonzalez W, Norenberg MD (2014) Sulfonylurea receptor I contributes to the astrocyte swelling and brain edema in acute liver failure. Trnsl Stroke Res 5:28–37
43. Jiang W, Desjardins P, Butterworth RF (2009a) Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem 109:485–493
44. Jiang W, Desjardins P, Butterworth RF (2009b) Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab 29:944–952
45. Kaplan MR, Plotkin MD, Brown D, Hebert SC, Delpire E (1996) Expression of the mouse Na-K-2Cl cotransporter, mBSC2, in the terminal inner medullary collecting duct, the glomerular and extraglomerular mesangium, and the glomerular afferent arteriole. J Clin Invest 98:723–730
46. Kato M, Sugihara J, Nakamura T, Muto Y (1989) Electron microscopic study of the blood–brain barrier in rats with brain edema and encephalopathy due to acute hepatic failure. Gastroenterol Jpn 24:135–142
47. 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
48. King LS, Agre P (1996) Pathophysiology of the aquaporin water channels. Annu Rev Physiol 58:619–648
49. Konopacka A, Konopacki FA, Albrecht J (2009) Protein kinase G is involved in ammonia-induced swelling of astrocytes. J Neurochem 109(Suppl 1):246–251
50. Kosenko E, Felipo V, Montoliu C, Grisolia S, Kaminsky Y (1996) Effects of acute hyperammonemia in vivo on oxidative metabolism in nonsynaptic rat brain mitochondria. Metab Brain Dis 12:69–82
51. Kosenko E, Kaminsky Y, Kaminsky A, Valencia M, Lee L, Hermenegildo C, Felipo V (1997) Superoxide production and antioxidant enzymes in ammonia intoxication in rats. Free Radic Res 27:637–644
52. Kramer L, Tribl B, Gendo A, Zauner C, Schneider B, Ferenci P, Madl C (2000) Partial pressure of ammonia versus ammonia in hepatic encephalopathy. Hepatology 31:30–34
53. Larsen FS, Wendon J (2008) Prevention and management of brain edema in patients with acute liver failure. Liver Transpl 14(Suppl 2):S90–S96
54. Larsen RH, Kjaer MS, Eefsen M, Larsen FS, Bjerring PN (2013) Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia. World J Hepatol 5:513–520
55. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM (2005) Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42:1364–1372
56. Lee WM (1994) Acute liver failure. Am J Med 96:3S–9S
57. Lee WL, Larson AM, Stravitz RT (2011) The management of acute liver failure: AASLD Position Paper. Hepatology www.aasld.org/practiceguidelines/Documents/AcuteLiverFailureUpdate2011.pdf
58. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163
59. Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195:1356–1358
60. Matkowskyj KA, Marrero JA, Carroll RE, Danilkovich AV, Green RM, Benya RV (1999) Azoxymethane-induced fulminant hepatic failure in C57BL/6J mice: characterization of a new animal model. Am J Physiol 277:G455–G462
61. Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, Davies NA, Jalan R (2007) Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 46:831–840
62. Murphy MG, Jollimore C, Crocker JF, Her H (1992) Beta-oxidation of [1-14C]palmitic acid by mouse astrocytes in primary culture: effects of agents implicated in the encephalopathy of Reye’s syndrome. J Neurosci Res 33:445–454
63. 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 66:282–288
64. Nguyen JH, Yamamoto S, Steers J, Sevlever D, Lin W, Shimojima N, Castanedes-Casey M, Genco P, Golde T, Richelson E, Dickson D, McKinney M, Eckman CB (2006) Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. J Hepatol 44:1105–1114
65. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180
66. Norenberg MD (1977) A light and electron microscopic study of experimental portal-systemic (ammonia) encephalopathy. Progression and reversal of the disorder. Lab Investig 36:618–627
67. Norenberg M (1981) Astrocytes in liver disease. In: Fedoroff S, Hertz L (eds) Adavnces in cellular neurobiology, vol 2. Academic Press, New York, pp 303–352
68. Norenberg MD, Rao KVR (2007) The mitochondrial permeability transition in neurologic disease. Neurochem Int 50:983–997
69. 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
70. Norenberg MD, Jayakumar AR, Rao KVR (2004) Oxidative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 19:313–329
71. Norenberg MD, Jayakumar AR, Reddy PV, Moriyama M, Panickar KS (2007) Oxidative/nitrosative stress, the permeability transition and map kinases in the mechanism of brain edema in acute liver failure. J Neurochem 102:25
72. Norenberg MD, Rama Rao KV, Jayakumar AR (2009) Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis 24:103–117
73. O’Connor JE, Costell M (1990) New roles of carnitine metabolism in ammonia cytotoxicity. Adv Exp Med Biol 272:183–195
74. Odeh M, Sabo E, Srugo I, Oliven A (2004) Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure. Liver Int 24:110–116
75. Olson JE, Evers JA, Holtzman D (1992) Astrocyte volume regulation and ATP and phosphocreatine concentrations after exposure to salicylate, ammonium, and fatty acids. Metab Brain Dis 7:183–196
76. Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, Arroliga AC, Mullen KD (2003) Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 114:188–193
77. Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14:265–277
78. Pasantes-Morales H (1996) Volume regulation in brain cells: cellular and molecular mechanisms. Metab Brain Dis 11:187–204
79. Pasantes-Morales H, Cruz-Rangel S (2010) Brain volume regulation: osmolytes and aquaporin perspectives. Neuroscience 168:871–884
80. Rai V, Nath K, Saraswat VA, Purwar A, Rathore RK, Gupta RK (2008) Measurement of cytotoxic and interstitial components of cerebral edema in acute hepatic failure by diffusion tensor imaging. J Magn Reson Imaging 28:334–341
81. Rama Rao KV, Chen M, Simard JM, Norenberg MD (2003a) Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport 14:2379–2382
82. Rama Rao KV, Chen M, Simard JM, Norenberg MD (2003b) Suppression of ammonia-induced astrocyte swelling by cyclosporin A. J Neurosci Res 74:891–897
83. Rama Rao KV, Jayakumar AR, Tong X, Alvarez VM, Norenberg MD (2010a) Marked potentiation of cell swelling by cytokines in ammonia-sensitized cultured astrocytes. J Neuroinflammation 7:66
84. Rama Rao KV, Jayakumar AR, Tong X, Curtis KM, Norenberg MD (2010b) Brain aquaporin-4 in experimental acute liver failure. J Neuropathol Exp Neurol 69:869–879
85. Rama Rao KV, Reddy PV, Tong X, Norenberg MD (2010c) Brain edema in acute liver failure: inhibition by L-histidine. Am J Pathol 176:1400–1408
86. Rama Rao KV, Verkman AS, Curtis KM, Norenberg MD (2013) Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure. Neurobiol Dis 63:222–228
87. Rangroo Thrane V, Thrane AS, Wang F, Cotrina ML, Smith NA, Chen M, Xu Q, Kang N, Fujita T, Nagelhus EA, Nedergaard M (2013) Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. Nat Med 19:1643–1648
88. Ranjan P, Mishra AM, Kale R, Saraswat VA, Gupta RK (2005) Cytotoxic edema is responsible for raised intracranial pressure in fulminant hepatic failure: in vivo demonstration using diffusion-weighted MRI in human subjects. Metab Brain Dis 20:181–192
89. Rao KV, Brahmbhatt M, Norenberg MD (2013) Microglia contribute to ammonia-induced astrocyte swelling in culture. Metab Brain Dis 28:139–143
90. Reddy PV, Murthy Ch R, Reddanna P (2004) Fulminant hepatic failure induced oxidative stress in nonsynaptic mitochondria of cerebral cortex in rats. Neurosci Lett 368:15–20
91. Reddy PV, Rama Rao KV, Norenberg MD (2009) Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes. J Neurosci Res 87:2677–2685
92. Ringel F, Bieringer F, Baethmann A, Plesnila N (2006) Effect of oxidative stress on glial cell volume. J Neurotrauma 23:1693–1704
93. Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia-Verdugo JM, Felipo V (2010) Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139:675–684
94. 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
95. Schliess F, Foster N, Görg B, Reinehr R, Häussinger D (2004) Hypoosmotic swelling increases protein tyrosine nitration in cultured rat astrocytes. Glia 47:21–29
96. Shah N, de Oca MM, Jover-Cobos M, Tanamoto KI, Muroi M, Sugiyama KI, Davies NA, Mookerjee RP, Dhar DK, Jalan R (2013) Role of toll-like receptor-4 in mediating multi-organ dysfunction in acetaminophen induced acute liver failure in mice. Liver Transpl 33:398–409
97. Shawcross D, Jalan R (2005) The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol Life Sci 62:2295–2304
98. Simard JM, Tsymbalyuk O, Ivanov A, Ivanova S, Bhatta S, Geng Z, Woo SK, Gerzanich V (2007) Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury. J Clin Invest 117:2105–2113
99. Sinke AP, Jayakumar AR, Panickar KS, Moriyama M, Reddy PV, Norenberg MD (2008) NFkappaB in the mechanism of ammonia-induced astrocyte swelling in culture. J Neurochem 106:2302–2311
100. Skowronska M, Albrecht J (2013) Oxidative and nitrosative stress in ammonia neurotoxicity. Neurochem Int 62:731–737
101. Staub F, Winkler A, Peters J, Kempski O, Baethmann A (1994) Mechanisms of glial swelling by arachidonic acid. Acta Neurochir Suppl (Wien) 60:20–23
102. Szumanska G, Albrecht J (1997) Lectin histochemistry of the rat brain following thioacetamide-induced hepatic failure. Mol Chem Neuropathol 32:163–177
103. Thumburu KK, Dhiman RK, Vasishta RK, Chakraborti A, Butterworth RF, Beauchesne E, Desjardins P, Goyal S, Sharma N, Duseja A, Chawla Y (2013) Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure. J Neurochem doi:10.1111/jnc.12511
104. Traber PG, Dal Canto M, Ganger DR, Blei AT (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
105. Traber P, DalCanto M, Ganger D, Blei AT (1989) Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization. Gastroenterology 96:885–891
106. Vaquero J, Butterworth RF (2007) Mechanisms of brain edema in acute liver failure and impact of novel therapeutic interventions. Neurol Res 29:683–690
107. Votyakova TV, Reynolds IJ (2005) Ca2+-induced permeabilization promotes free radical release from rat brain mitochondria with partially inhibited complex I. J Neurochem 93:526–537
108. Walcott BP, Kahle KT, Simard JM (2012) Novel treatment targets for cerebral edema. Neurotherapeutics 9:65–72
109. Ware AJ, D’Agostino AN, Combes B (1971) Cerebral edema: a major complication of massive hepatic necrosis. Gastroenterology 61:877–884
110. Warskulat U, Görg B, Bidmon HJ, Muller HW, Schliess F, Häussinger D (2002) Ammonia-induced heme oxygenase-1 expression in cultured rat astrocytes and rat brain in vivo. Glia 40:324–336
111. Wilkinson SP, Arroyo V, Moodie H, Williams R (1974) Proceedings: endotoxaemia in fulminant hepatic failure. Clin Sci Mol Med 46:30P–31P
112. Wyke RJ, Canalese JC, Gimson AE, Williams R (1982) Bacteraemia in patients with fulminant hepatic failure. Liver 2:45–52
113. Zemtsova I, Görg B, Keitel V, Bidmon HJ, Schror K, Häussinger D (2011) Microglia activation in hepatic encephalopathy in rats and humans. Hepatology 54:204–215
114. Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241:139–176
115. Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ (2000) Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 192:1001–1014
116. Zwingmann C, Flogel U, Pfeuffer J, Leibfritz D (2000) Effects of ammonia exposition on glioma cells: changes in cell volume and organic osmolytes studied by diffusion-weighted and high-resolution NMR spectroscopy. Dev Neurosci 22:463–471