Neurosteroids and hepatic encephalopathy: An update on possible pathophysiologic mechanisms

Current Molecular Pharmacology

Volumn 4, Issue 1, 2011, Pages 1-13

  Ahboucha, Samir ^a  

^a FACULTÉ DES SCIENCES SEMLALIA   (Morocco)

Author keywords

Ammonia; Cytokines; Gene expression; Hepatic encephalopathy; Manganese; Neurosteroids; Neurotransmission; TSPO

Indexed keywords

4 AMINOBUTYRIC ACID RECEPTOR; AMMONIA; BENZODIAZEPINE; BRAIN RECEPTOR; CARRIER PROTEIN; MANGANESE; NEUROSTEROID; NEUROTRANSMITTER RECEPTOR;

ARTICLE; BIOSYNTHESIS; GENE EXPRESSION; HEPATIC ENCEPHALOPATHY; HUMAN; INFLAMMATION; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; STEROID BLOOD LEVEL; STEROIDOGENESIS;

EID: 78650860660     PISSN: 18744672     EISSN: 18744702     Source Type: Journal    
DOI: 10.2174/1874467211104010001     Document Type: Article

References (125)

1. Blei, A.T. Brain edema in acute liver failure. Crit. Care Clin., 2008, 24, 99-114.
2. Ferenci, P.; Lockwood, A.H.; Mullen, K.; Tarter, R.; Weissenborn, K.; Blei, A.T. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th World Congress of Gastroenterology, Vienna 1998. Hepatology, 2002, 35, 716-721.
3. Weissenborn, K.; Giewekemeyer, K.; Heidenreich, S.; Bokemeyer, M.; Berding, G.; Ahl, B. Attention, memory, and cognitive function in hepatic encephalopathy. Metab. Brain Dis., 2005, 20, 359-367.
4. Ahboucha, S.; Butterworth, R.F. Pathophysiology of hepatic encephalopathy: a new look at GABA from the molecular standpoint. Metab. Brain Dis., 2004, 19, 331-343.
5. Zaman, S.H. Endogenous steroids and pathogenesis of hepatic encephalopathy. Lancet, 1990, 336, 573-574.
6. Jones, E.A. Potential mechanisms of enhanced GABA-mediated inhibitory neurotransmission in liver failure. Neurochem. Int., 2003, 43, 509-516.
7. Norenberg, M.D. Astroglial dysfunction in hepatic encephalopathy. Metab. Brain Dis., 1998, 13, 319-335.
8. Corpéchot, C.; Robel, P.; Axelson, M.; Sjövall, J.; Baulieu, E.E. Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc. Natl. Acad. Sci. USA, 1981, 78, 4704-4707.
9. Corpéchot, C.; Synguelakis, M.; Talha, S.; Axelson, M.; Sjövall, J.; Vihko, R.; Baulieu, E.E.; Robel, P. Pregnenolone and its sulfate ester in the rat brain. Brain Res., 1983, 270, 119-125.
10. Cheney, D.L.; Uzunov, D.; Costa, E.; Guidotti, A. Gas chromatographic-mass fragmentographic quantitation of 3a-hydroxy-5a-pregnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats. J. Neurosci., 1995, 15, 4641-4650.
11. Baulieu, E.E.; Robel, P. Neurosteroids: a new brain function? J. Steroid Biochem. Mol. Biol., 1990, 37, 395-403.
12. Robel, P.; Baulieu, E.E. Neurosteroids: biosynthesis and function. Trends Endocrinol. Metab., 1994, 5, 1-8.
13. Mensah-Nyagan, A.G.; Do-Rego, J.L.; Beaujean, D.; Luu-The, V.; Pelletier, G.; Vaudry, H. Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol. Rev., 1999, 51, 63-81.
14. Mellon, S.; Vaudry, H. Biosynthesis of neurosteroids and regulation of their synthesis. Int. Rev. Neurobiol., 2001, 46, 33-78.
15. Do Rego, J.L.; Seong, J.Y.; Burel, D.; Leprince, J.; Luu-The, V.; Tsutsui, K.; Tonon, M.C.; Pelletier, G.; Vaudry, H. Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front. Neuroendocrinol., 2009, 30, 259-301.
16. Kimoto, T.; Tsurugizawa, T.; Ohta, Y.; Makino, J.; Tamura, H.; Hojo, Y.; Takata, N.; Kawato, S. Neurosteroid synthesis by cyto-chrome p450-containing systems localized in the rat brain hippo-campal neurons: N-methyl-D-aspartate and calcium-dependent synthesis. Endocrinology, 2001, 142, 3578-3589.
17. Agís-Balboa, R.C.; Pinna, G.; Zhubi, A.; Maloku, E.; Veldic, M.; Costa, E.; Guidotti, A. Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc. Natl. Acad. Sci. USA, 2006, 103, 14602-14607.
18. Tsutsui, K.; Yamazaki, T. Avian neurosteroids I. Pregnenolone biosynthesis in the quail brain. Brain Res., 1995, 678, 1-9.
19. Ukena, K.; Honda, Y.; Inai, Y.; Kohchi, C.; Lea, R.W.; Tsutsui, K. Expression and activity of 3b-hydroxysteroid dehydrogenase/D5- D4 isomerase in different regions of the avian brain. Brain Res., 1999, 818, 536-542.
20. Ukena, K.; Honda, Y.; Lea, R.W.; Tsutsui, K. Developmental changes in progesterone biosynthesis and metabolism in the quail brain. Brain Res., 2001, 898, 190-194.
21. Papadopoulos, V.; Baraldi, M.; Guilarte, TR.; Knudsen, T.B.; La-capere, J.J.; Lindemann, P.; Norenberg, M.D.; Nutt, D.; Weizman, A.; Zhang, M.R.; Gavish, M. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol., Sci., 2006, 27, 402-409.
22. McEnery, M.W.; Snowman, A.M.; Trifiletti, R.R.; Snyder, S.H. Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleo-tide carrier. Proc. Natl. Acad. Sci. USA, 1992, 89, 3170-3174.
23. Korneyev, A.; Pan, B.S.; Polo, A.; Romeo, E.; Guidotti, A.; Costa, E. Stimulation of brain pregnenolone synthesis by mitochondrial diazepam binding inhibitor receptor ligands in vivo. J. Neurochem., 1993, 61, 1515-1524.
24. Papadopoulos, V.; Guarneri, P.; Kreuger, K.E.; Guidotti, A.; Costa, E. Pregnenolone biosynthesis in C6-2B glioma cell mitochondria: regulation by a mitochondrial diazepam binding inhibitor receptor. Proc. Natl. Acad. Sci. USA, 1992, 89, 5113-5117.
25. Do Rego, J.L.; Mensah-Nyagan, A.G.; Feuilloley, M.; Ferrara, P.; Pelletier, G.; Vaudry, H. The endozepine triakontatetraneuropeptide diazepam-binding inhibitor stimulates neurosteroid biosynthesis in the frog hypothalamus. Neuroscience, 1998, 83, 555-570.
26. Do Rego, J.L.; Leprince, J.; Luu-The, V.; Pelletier, G.; Tonon, M.C.; Vaudry, H. Structure-activity relationships of a series of analogs of the endozepine octadecaneuropeptide (ODN11-18) on neurosteroid biosynthesis by hypothalamic explants. J. Med. Chem., 2007, 50, 3070-3076.
27. Sierra, A. Neurosteroids: The StAR Protein in the Brain. J. Neuroendocrinol., 2004, 16, 787-793.
28. Norenberg, M.D.; ltzhak, Y.; Bender, A.S. The peripheral benzodi-azepine receptor and neurosteroids in hepatic encephalopathy. Adv. Exp. Med. Biol., 1997, 420, 95-111.
29. Bélanger, M.; Desjardins, P.; Chatauret, N.; Rose, C.; Butterworth, R.F. Mild hypothermia prevents brain edema and attenuates up-regulation of the astrocytic benzodiazepine receptor in experimental acute liver failure. J. Hepatol., 2005, 42, 694-699.
30. Ahboucha, S.; Pomier-Layrargues, G.; Mamer, O.; Butterworth, R.F. Increased levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma. Neurochem. Int., 2006, 49, 372-378.
31. Ahboucha, S.; Jiang, W.; Chatauret, N.; Mamer, O.; Baker, G.B.; Butterworth R.F. Indomethacin improves locomotor deficit and reduces brain concentrations of neuroinhibitory steroids in rats following portacaval anastomosis. Neurogastroenterol. Motil., 2008, 20, 949-957.
32. Ahboucha, S.; Layrargues, G.P.; Mamer, O.; Butterworth, R.F. Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann. Neurol., 2005, 58, 169-170.
33. Mellon, S.H.; Miller, W.L. Extra-adrenal steroid 21-hydroxylation is not mediated by P450c21. J. Clin. Invest., 1989, 84, 1497-1502.
34. Eser, D.; di Michele, F.; Zwanzger, P.; Pasini, A.; Baghai, T.C.; Schüle, C.; Rupprecht, R.; Romeo, E. Panic induction with chole-cystokinin-tetrapeptide (CCK-4) Increases plasma concentrations of the neuroactive steroid 3alpha, 5alpha tetrahydrodeoxycorticosterone (3alpha, 5alpha-THDOC) in healthy volunteers. Neuropsy-chopharmacol., 2005, 30, 192-195.
35. Liere, P.; Pianos, A.; Eychenne, B.; Cambourg, A.; Liu, S.; Griffiths, W.; Schumacher, M.; Sjövall, J.; Baulieu, E.E. Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain. J. Lipid Res., 2004, 45, 2287-302.
36. Ahboucha, S.; Baker, B.G.; Pomier-Layrargues, G.; Butterworth R.F. Alterations of brain levels of neuroactive steroids allopreg-nanolone and dehydroepinadrosterone sulphate in patients who died in hepatic coma: Further evidence for "increased GABAergic tone" in hepatic encephalopathy. Can. J. Gastroenterol., 2008, 22, suppl SA. 028.
37. Rupprecht, R.; Holsboer, F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neu-rosc., 1999, 22, 410-416.
38. Fodor, L.; Biro, T.; Maksay, G. Nanomolar allopregnanolone potentiates rat cerebellar GABAA receptors. Neurosci. Lett., 2005, 383, 127-130.
39. Wang, M.D.; Bäckström, T.; Landgren, S. The inhibitory effects of allopregnanolone and pregnanolone on the population spike, evoked in the rat hippocampal CA1 stratum pyramidale in vitro, can be blocked selectively by epiallopregnanolone. Acta Physiol. Scand., 2000, 169, 333-341.
40. Lan, N.C.; Gee, K.W.; Bolger, M.B.; Chen, J.S. Differential responses of expressed recombinant human g-aminobutyric acid-A receptors to neurosteroids. J. Neurochem., 1991, 57, 1818-1821.
41. Belelli, D.; Casula, A.; Ling, A.; Lambert, J.J. The influence of subunit composition on the interaction of neurosteroids with GABAA receptors. Neuropharmacol., 2002, 43, 651-661.
42. Majewska, M.D.; Demirgoren, S.; Spivak, C.E.; London, E.D. The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABA(A) receptor. Brain Res., 1990, 526, 143-146.
43. Scollo-Lavizzari, G.; Steinmann, E. Reversal of hepatic coma by benzodiazepine antagonist (RO 15-1788). Lancet, 1985, 1, 1324.
44. Goulenok, C.; Bernard, B.; Cadranel, J.F.; Thabut, D.; Di Martino, V.; Opolon, P.; Poynard, T. Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis. Alimentary Pharmacol. Therap., 2002, 16, 361-372.
45. Ahboucha, S.; Butterworth, R.F. Role of endogenous benzodi-azepine ligands and their GABAA-associated receptors in hepatic encephalopathy. Metab. Brain Dis., 2005, 20, 425-437.
46. Harrison, N.L.; Majewska, M.D.; Harrington, J.W.; Barker, J.L. Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. J. Pharmacol. Exp. Therap., 1987, 241, 346-353.
47. Ahboucha, S.; Desjardins, P.; Chatauret, N.; Pomier-Layrargues, G.; Butterworth, R.F. Normal coupling of brain benzodiazepine and neurosteroid modulatory sites on the GABAA receptor complex in human hepatic encephalopathy. Neurochem. Int., 2003, 43, 551-556
48. Ahboucha, S.; Butterworth, R.F. The neurosteroid system: Implication in the pathophysiology of hepatic encephalopathy. Neurochem. Int., 2008, 52, 575-587.
49. Bonetti, E.P.; Burkard, W.P.; Gabl, M.; Hunkeler, W.; Lorez, H.P.; Martin, J.R.; Moehler, H.; Osterrieder, W.; Pieri, L.; Polc, P.; Richards, J.G.; Schaffener, R.; Scherschlicht, R.; Schoch, P.; Haefely, W.E. Ro 15-4513: partial inverse agonism at the BZR and interaction with ethanol. Pharmacol. Biochem. Behav., 1988, 31, 733-749.
50. Ahboucha, S.; Coyne, L.; Hirakawa, R.; Butterworth, R.F.; Halli-well, R.F. An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons. Neurochem. Int., 2006, 48, 703-707.
51. Hazell, A.S.; Butterworth, R.F. Hepatic encephalopathy: An update of pathophysiologic mechanisms. Proc. Soc. Exp. Biol. Med., 1999, 222, 99-112.
52. Bacci, A.; Huguenard, J.R.; Prince, D.A. Modulation of neocortical interneurons: extrinsic influences and exercises in self-control. Trends Neurosci., 2005, 28, 602-610.
53. Fedele, E.; Ansaldo, M.A.; Varnier, G.; Raiteri, M. Benzodi-azepine-sensitive GABA(A) receptors limit the activity of the NMDA/NO/cyclic GMP pathway: a microdialysis study in the cerebellum of freely moving rats. J. Neurochem., 2000, 75, 782-787.
54. Pepicelli, O.; Brescia, A.; Gherzi, E.; Raiteri, M.; Fedele, E. GABA(A), but not NMDA, receptors modulate in vivo NO-mediated cGMP synthesis in the rat cerebral cortex. Neuropharmacology, 2004, 46, 480-489.
55. Cauli, O.; Mansouri, M.T.; Agusti, A.; Felipo, V. Hyperammonemia increases GABAergic tone in the cerebellum but decreases it in the rat cortex. Gastroenterology, 2009, 136, 1359-1367.
56. Gartside, S.; Griffith, N.; Kaura, V.; Ingram, C. The neurosteroid dehydroepiandrosterone (DHEA) and its metabolites alter 5-HT neuronal activity via modulation of GABAA receptors. J. Psycho-pharmacol., 2009, Online published on June 3, doi:10.1177/0269881109105836.
57. Yurdaydin, C.; Herneth, A.M.; Puspok, A.; Steindl, P.; Singer, E.; Ferenci, P. Modulation of hepatic encephalopathy in rats with thioacetamide-induced acute liver failure by serotonin antagonists. Eur. J. Gastroenterol. Hepatol., 1996, 8, 667-671.
58. Nguyen, H.; Wang, H.; le, T.; Ho, W.; Sharkey, K.A.; Swain, M.G. Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats. Neurogastroenterol. Motil., 2008, 20, 228-235.
59. Swain, M.G.; Maric, M. Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. Hepatology, 1997, 25, 291-294.
60. Celik, T.; Goren, M.Z.; Cinar, K.; Gurdal, H.; Onder, F.O.; Tan, A.; Terzioglu, B.; Bozdayi, A.M.; Bozkaya, H.; Uzunalimoglu, O.; Yurdaydin, C. Fatigue of cholestasis and the serotoninergic neuro-transmitter system in the rat. Hepatology, 2005, 41, 731-737.
61. Butterworth, R.F.; Lalonde, R.; Power, C.; Baker, G.B.; Gamrani, H.; Ahboucha, S. Dehydroepiandrosterone sulphate improves cholestasis-associated fatigue in bile duct ligated rats. Neurogastroenterol. Motil., 2009, 21, 1319-1325.
62. Jones, E.A. Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. Lancet, 1999, 354 (9176), 397.
63. Piche, T.; Vanbiervliet, G.; Cherikh, F.; Antoun, Z.; Huet, P.M.; Gelsi, E.; Demarquay, J.F.; Caroli-Bosc, F.X.; Benzaken, S.; Rigault, M.C.; Renou, C.; Rampal, P.; and Tran, A. Effect of ondan-setron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. Gut, 2005, 54, 1169-1173.
64. Theal, J.J.; Toosi, M.N.; Girlan, L.; Heslegrave, R.J.; Huet, P.M.; Burak, K.W.; Swain, M.; Tomlinson, G.A.; Heathcote, E.J. A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue. Hepatology, 2005, 41, 1305-1312.
65. Ahboucha, S.; Pomier-Layrargues, G.; Vincent, C.; Hassoun, Z.; Tamaz, R.; Baker, G.; Butterworth, R.F. Reduced plasma dehy-droepiandrosterone sulfate levels are significantly correlated with fatigue severity in patients with primary biliary cirrhosis. Neuro-chem. Int., 2008, 52, 569-74.
66. Rupprecht, R.; Reul, J.M.; Trapp, T.; van Steensel, B.; Wetzel, C.; Damm, K.; Zieglgansberger, W.; Holsboer, F. Progesterone receptor-mediated effects of neuroactive steroids. Neuron, 1993, 11, 523-530.
67. Desjardins, P.; Bélanger, M.; Butterworth, R.F. Alterations in expression of genes coding for key astrocytic proteins in acute liver failure. J. Neurosc. Res., 2001, 66, 967-971.
68. Butterworth, R.F. Alterations of neurotransmitter-related gene expression in human and experimental portal-systemic encephalopathy. Metabol. Brain Dis., 1998, 13, 337-349.
69. Lamba, V.; Yasuda, K.; Lamba, J.K.; Assem, M.; Davila, J.; Strom, S.; Schuetz, E.G. PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol. Appl. Pharmacol., 2004, 199, 251-265.
70. Bender, A.S.; Norenberg, M.D. Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes. J. Neurosci. Res., 1998, 54, 673-680.
71. Desjardins, P.; Butterworth, R.F. The peripheral-type benzodi-azepine (omega 3) receptor in hyperammonemic disorders. Neuro-chem. Int., 2002, 41, 109-114.
72. Lavoie, J.; Pomier Layrargues, G.; Butterworth, R.F. Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology, 1990, 11, 874-878.
73. Bélanger, M.; Ahboucha, S.; Desjardins, P.; Butterworth, R.F. Upregulation of peripheral-type (mitochondrial) benzodiazepine receptors in hyperammonemic syndromes: consequences for neuronal excitability. Adv. Mol. Cell Biol., 2004, 31, 983-997.
74. Cagnin, A.; Taylor-Robinson, S.D.; Forton, D.M.; Banati, R.B. In vivo imaging of cerebral peripheral benzodiazepine binding sites in patients with hepatic encephalopathy. Gut, 2006, 55, 547-553.
75. Iversen, P.; Hansen, D.A.; Bender, D.; Rodell, A.; Munk, O.L.; Cumming, P.; Keiding, S. Peripheral benzodiazepine receptors in the brain of cirrhosis patients with manifest hepatic encephalopathy. Eur. J. Nucl. Med. Mol. Imaging, 2006, 33, 810-816.
76. Raghavendra Rao, V.L.; Audet, R.; Therrien, G.; Butterworth, R.F. Tissue-specific alterations of binding sites for peripheral-type ben-zodiazepine receptor ligand [3H]PK11195 in rats following portacaval anastomosis. Dig. Dis. Sci., 1994, 39, 1055-1063.
77. Leong, D.K.; Therrien, G.; Swain, M.S.; Butterworth, R.F. Densities of binding sites for the "peripheral-type" benzodiazepine receptor ligand 3H-PK11195 are increased in brain 24 hours following portacaval anastomosis. Metab. Brain Dis., 1994, 9, 267-273.
78. Giguère, J.F.; Hamel, E.; Butterworth, R.F. Increased densities of binding sites for the "peripheral-type" benzodiazepine receptor ligand [3H]PK11195 in rat brain following portacaval anastomosis. Brain Res., 1992, 585, 295-298.
79. Desjardins, P.; Bandeira, P.; Raghavendra Rao, V.L.; Butterworth, R.F. Portacaval anastomosis causes selective alterations of peripheral-type benzodiazepine receptor expression in rat brain and peripheral tissues. Neurochem. Int., 1999, 35, 293-299.
80. Itzhak, Y.; Roig-Cantisano, A.; Dombro, R.S.; Norenberg, M.D. Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain. Brain Res., 1995, 705, 345-348.
81. Kadota, Y.; Inoue, K.; Tokunaga, R.; Taketani, S. Induction of peripheral-type benzodiazepine receptors in mouse brain following thioacetamide-induced acute liver failure. Life Sci., 1996, 58, 953-959.
82. Casellas, P.; Galiegue, S.; Basile, A.S. Peripheral benzodiazepine receptors and mitochondrial function. Neurochem. Int., 2002, 40, 475-486.
83. Alho, H.; Fremeau, R.T. Jr.; Tiedge, H.; Wilcox, J.; Bovolin, P.; Brosius, J.; Roberts, J.L.; Costa, E. Diazepam binding inhibitor gene expression: location in brain and peripheral tissues of rat. Proc. Natl. Acad. Sci. USA, 1988, 85, 7018-7022.
84. Alho, H.; Harjuntausta, T.; Schultz, R.; Pelto-Huikko, M.; Bovolin, P. Immunohistochemistry of diazepam binding inhibitor (DBI) in the central nervous system and peripheral organs: its possible role as an endogenous regulator of different types of benzodiazepine receptors. Neuropharmacology, 1991, 30, 1381-1386.
85. Costa, E.; Guidotti, A. Diazepam binding inhibitor (DBI): a peptide with multiple biological actions. Life Sci., 1991, 49, 325-344.
86. Rothstein, J.D.; McKhann, G.; Guarneri, P.; Barbaccia, M.L.; Guidotti, A.; Costa, E. Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy. Ann. Neurol., 1989, 26, 57-62.
87. Guidotti, A.; Berkovich, A.; Ferrarese, C.; Santi, M.R.; Costa, E. Neuronal-glial diffential processing of DBI to yield ligands to central or peripheral benzodiazepine recognition sites; Sauvenet, P.; Langer, S.Z.; Morselli, P.L. Eds.; Raven Press: New York, 1988, pp. 25-38.
88. Butterworth, R.F.; Tonon, M.C.; Désy, L.; Giguère, J.F.; Vaudry, H.; Pelletier, G. Increased brain content of the endogenous benzo-diazepine receptor ligand, octadecaneuropeptide (ODN), following portacaval anastomosis in the rat. Peptides, 1991, 12, 119-125.
89. Cagnon, L.; Braissant, O. Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res. Rev., 2007, 56, 183-197.
90. Felipo, V.; Butterworth, R.F. Neurobiology of ammonia. Prog. Neurobiol., 2002, 67, 259-279.
91. Raghavendra Rao, V.L.; Qureshi, I.A.; Butterworth, R.F. Increased densities of binding sites for the peripheral-type benzodiazepine receptor ligand [3H]PK11195 in congenital ornithine transcarbamylase-deficient sparse fur mouse. Pediatr. Res., 1993, 34, 777-780.
92. Itzhak, Y.; Norenberg, M.D. Ammonia-induced upregulation of peripheral-type benzodiazepine receptors in cultured astrocytes la-belled with [3H]PK11195. Neurosci. Lett., 1994, 177, 35-38.
93. Hazell, A.S. Astrocytes and manganese neurotoxicity. Neurochem. Int., 2002, 41, 271-277.
94. Rose, C.; Butterworth, R.F.; Zayed, J.; Normandin, L.; Todd, K.; Michalak, A.; Spahr, L.; Huet, P.M.; Pomier-Layrargues, G. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology, 1999, 117, 640-644.
95. Layrargues, G.P.; Shapcott, D.; Spahr, L.; Butterworth, R.F. Accumulation of manganese and copper in pallidum of cirrhotic patients: role in the pathogenesis of hepatic encephalopathy? Metab. Brain Dis., 1995, 10, 353-356.
96. Hazell, A.S.; Desjardins, P.; Butterworth, R.F. 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., 1999, 271, 5-8.
97. Hazell, A.S.; Normandin, L.; Nguyen, B.; Kennedy, G. Upregulation of "peripheral-type" benzodiazepine receptors in the globus pallidus in a sub-acute rat model of manganese neurotoxicity. Neurosci. Lett., 2003, 349, 13-16.
98. Hazell, A.S.; Normandin, L.; Norenberg, M.D.; Kennedy, G.; Yi, J.H. Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment. Neurosci. Lett., 2006, 396, 167-171.
99. Nelson, K.; Golnick, J.; Korn, T.; Angle, C. Manganese encephalopathy: Utility of early magnetic resonance imaging. Br. J. Ind. Med., 1993, 50, 510-513.
100. Newland, M.C.; Ceckler, T.L.; Kordower, J.H.; Weiss, B. Visualizing manganese in the primate basal ganglia with magnetic resonance imaging. Exp. Neurol., 1989, 106, 251-258.
101. Kulisevsky, J.; Pujol, J.; Junqué, C.; Deus, J.; Balanzó, J.; Capdevila, A. MRI pallidal hyperintensity and brain atrophy in cirrhotic patients: two different MRI patterns of clinical deterioration? Neurology, 1993, 43, 2570-2573.
102. Forton, D.M.; Patel, N.; Prince, M.; Oatridge, A.; Hamilton, G.; Goldblatt, J.; Allsop, J.M.; Hajnal, J.V.; Thomas, H.C.; Bassendine, M.; Jones, D.E.; Taylor-Robinson, S.D. Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels. Gut, 2004, 53, 587-592.
103. Becker, U.; Almdal, T.; Christensen, E.; Gluud, C.; Farholt, S.; Bennett, P.; Svenstrup B.; Hardt F. Sex hormones in postmeno-pausal women with primary biliary cirrhosis. Hepatology, 1991, 13, 865-869.
104. Franz, C.; Watson, D.; Longcope, C. Estrone sulfate and dehydroepiandrosterone sulfate concentrations in normal subjects and men with cirrhosis. Steroids, 1979, 34, 563-573.
105. Farthing, M.J.; Green, J.R.; Edwards, C.R.; Dawson, A.M. Proges-terone, prolactin, and gynaecomastia in men with liver disease. Gut, 1982, 23, 276-279.
106. Lustik, S.J.; Chhibber, A.K.; Kolano, J.W.; Hilmi, I.A.; Henson, L.C.; Morris, M.C.; Bronsther, O. The hyperventilation of cirrhosis: progesterone and estradiol effects. Hepatology, 1997, 25, 55-58.
107. Aller, R.; de Luis, D.A.; Moreira, V.; Boixeda, D.; Moya, J.L.; Fernandez-Rodriguez, C.M.; San Roman, A.L.; Avila, S.; Barcena, R. The effect of liver transplantation on circulating levels of estradiol and progesterone in male patients: parallelism with hepato-pulmonary syndrome and systemic hyperdynamic circulation improvement. J. Endocrinol. Invest., 2001, 24, 503-509.
108. Shawcross, D.; Jalan, R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol. Life Sci., 2005, 62, 2295-2304.
109. Rolando, N.; Wade, J.; Davalos, M.; Wendon, J.; Philpott-Howard, J.; Williams, R. The systemic inflammatory response syndrome in acute liver failure. Hepatology, 2000, 32, 734-739.
110. Shawcross, D.L.; Davies, N.A.; Williams, R.; Jalan, R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J. Hepatol., 2004, 40, 247-254.
111. Jiang, W.; Desjardins, P.; Butterworth, R.F. Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J. Cereb. Blood Flow Metab., 2009, 29, 944-952.
112. Cauli, O.; Rodrigo, R.; Piedrafita, B.; Boix, J.; Felipo, V. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology, 2007, 46, 514-519.
113. Rodrigo, R.; Cauli, O.; Gomez-Pinedo, U.; Agusti, A.; Hernandez- Rabaza, V.; Garcia-Verdugo, J.M.; Felipo, V. Hyperammonemia Induces Neuroinflammation That Contributes to Cognitive Impairment in Rats With Hepatic Encephalopathy. Gastroenterology, 2010, [in press].
114. Cagnin, A.; Kassiou, M.; Meikle, S.R.; Banati, R.B. Positron emission tomography imaging of neuroinflammation. Neurotherapeutics, 2007, 4, 443-452.
115. Colton, C.A; Wilcock, D.M. Assessing activation states in microglia. CNS Neurol. Disord. Drug Targets, 2010, 9, 174-191.
116. Norenberg, M.D.; Jayakumar, A.R.; Rama Rao, K.V.; Panickar, K.S. The peripheral benzodiazepine receptor and neurosterois in the pathogenesis of hepatic encephalopathy and ammonia neurotoxcity; Häussinger, D., Kircheis G., Schliess, F., Eds.; Springer: Berlin, 2006, pp.143-159.
117. Bourdiol, F.; Toulmonda, S.; Serranoa, A.; Benavides, J.; Scattona, B. Increase in 3 (peripheral type benzodiazepine) binding sites in the rat cortex and striatum after local injection of interleukin-1, tumour necrosis factor-and lipopolysaccharide. Brain Res., 1991, 543, 194-200.
118. Oh, Y.J.; Francis, J.W.; Markelonis, G.J.; Oh, T.H. Interleukin-1- and tumor necrosis factor-increase peripheral-type benzodi-azepine binding sites in cultured polygonal astrocytes. J. Neuro-chem., 1992, 58, 2131-2138.
119. Ghezzi, P.; Santo, E.D.; Sacco, S.; Foddi, C.; Barbaccia, M.L.; Mennini, T. Neurosteroid levels are increased in vivo after LPS treatment and negatively regulate LPS-induced TNF production. Eur. Cytokine Netw., 2000, 11, 464-469.
120. Billiards, S.S.; Nguyen, P.N.; Scheerlinck, J.P.; Phillips, D.J.; Canny, B.J.; Walker, D.W.; Hirst, J.J. Hypoxia potentiates endotoxin-induced allopregnanolone concentrations in the newborn brain. Biol. Neonate, 2006, 90, 258-267.
121. Butterworth, R.F. Neuronal cell death in hepatic encephalopathy. Metab. Brain Dis., 2007, 22, 309-320.
122. Müller, E.; Kerschbaum, H.H. Progesterone and its metabolites 5- dihydroprogesterone and 5-3-tetrahydroprogesterone decrease LPS- induced NO release in the murine microglial cell line, BV-2. Neuro Endocrinol. Lett., 2006, 27, 675-678.
123. Butterworth, R.F. Pathophysiology of hepatic encephalopathy: The concept of synergism. Hepatol. Res., 2008, 38, S116-S121.
124. Zhu, D.; Wang, M.D.; Bäckström, T.; Wahlström, G. Evaluation and comparison of the pharmacokinetic and pharmacodynamic properties of allopregnanolone and pregnanolone at induction of anaesthesia in the male rat. Br. J. Anaesth., 2001, 86, 403-412.
125. Kato, M.; Hughes, R.D.; Keays, R.T.; Williams, R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology, 1992, 15, 1060-1066.