Role of endogenous benzodiazepine ligands and their GABA-A-associated receptors in hepatic encephalopathy

Metabolic Brain Disease

Volumn 20, Issue 4, 2005, Pages 425-437

  Ahboucha, Samir ^a   Butterworth, Roger F ^a  

^a UNIVERSITY OF MONTREAL   (Canada)

Author keywords

11C flumazenil; Antagonists; Benzodiazepines; GABA A receptors; Hepatic encephalopathy; Inverse agonists

Indexed keywords

2 PHENYL 5H PYRAZOLO[4,3 C]QUINOLIN 3 ONE; 4 AMINOBUTYRIC ACID A RECEPTOR; 4 ETHYL 6,7 DIMETHOXY BETA CARBOLINE 3 CARBOXYLIC ACID METHYL ESTER; 8 AZIDO 5,6 DIHYDRO 5 METHYL 6 OXO 4H IMIDAZO[1,5 A][1,4]BENZODIAZEPINE 3 CARBOXYLIC ACID ETHYL ESTER; AMMONIA; BARBITURIC ACID DERIVATIVE; BENZODIAZEPINE DERIVATIVE; BENZODIAZEPINE RECEPTOR; BENZODIAZEPINE RECEPTOR BLOCKING AGENT; BENZODIAZEPINE RECEPTOR STIMULATING AGENT; FLUMAZENIL; FLUNITRAZEPAM; NEUROSTEROID; PICROTOXIN; RO 14 7437; SARMAZENIL;

BEHAVIOR; BINDING AFFINITY; CLINICAL TRIAL; COMPLEX FORMATION; CONFERENCE PAPER; DRUG BINDING SITE; DRUG CLEARANCE; DRUG EFFECT; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG UPTAKE; ELECTROPHYSIOLOGY; GABAERGIC TRANSMISSION; HEPATIC ENCEPHALOPATHY; HUMAN; META ANALYSIS; NONHUMAN; PATHOGENESIS; RECEPTOR BINDING; RECEPTOR DENSITY; SYSTEMATIC REVIEW; TREATMENT OUTCOME;

ANIMALS; BENZODIAZEPINES; HEPATIC ENCEPHALOPATHY; HUMANS; LIGANDS; RECEPTORS, GABA-A;

EID: 29744466907     PISSN: 08857490     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11011-005-7928-y     Document Type: Conference Paper

References (57)

1. Ahboucha, S., Araqi, F., Pomier-Layrargues, G., and Butterworth, R.F. (2005a). Differential effects of ammonia on the benzodiazepine modulatory site on the GABA-A receptor complex of human brain. Neurochem. Int. 47:58-63.
2. Ahboucha, S., and Butterworth, R.F. (2004). Pathophysiology of hepatic encephalopathy: A new look at GABA from the molecular standpoint. Metab. Brain Dis. 19:331-343.
3. Ahboucha, S., Desjardins, P., Chatauret, N., Pomier-Layrargues, G., and Butterworth, R.F. (2003). Normal coupling of brain benzodiazepine and neurosteroid modulatory sites on the GABA-A receptor complex in human hepatic encephalopathy. Neurochem. Int. 43:551-556.
4. Ahboucha, S., Layrargues, G.P., Mamer, O., and Butterworth, R.F. (2005b). Increased concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann. Neurol. 58:169-170.
5. Ahboucha, S., Pomier-Layrargues, G., and Butterworth, R.F. (2004). Increased brain concentrations of endogenous (non-benzodiazepine) GABA-A receptor ligands in human hepatic encephalopathy. Metab. Brain Dis. 19:241-251.
6. Bansky, G., Meier, P.S., Ziegler, W.H., Walser, H., Schmid, H., and Huber, M. (1985). Reversal of hepatic coma by benzodiazepine antagonists (Rol5-1788). Lancet 1:1324-1325.
7. Baraldi, M., Zeneroli, M.L., Ventura, E., Penne, A., Pinelli, G., Ricci, P., and Santi, M. (1984). Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: Reversal by a benzodiazepine antagonist. Clin. Sci. 67:167-175.
8. Barbaro, G., Di Lorenzo, G., Soldini, M., Giancaspro, G., Bellomo, G., Belloni, G., Grisorio, B., Annese, M., Bacca, D., Francavilla, R., and Barbarini, G. (1998). Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: An Italian multicenter double-blind, placebo-controlled, cross-over study. Hepatology 28:374-378.
9. Basile, A.S., Gammal, S.H., Mullen, K.D., Jones, E.A., and Skolnick, P. (1988). Differential responsiveness of cerebellar Purkinje neurons to GABA and benzodiazepine receptor ligands in an animal model of hepatic encephalopathy. J. Neurosci. 8:2414-2421.
10. Basile, A.S., Hughes, R.D., Harrison, P.M., Murata, Y., Pannell, L., Jones, E.A., Williams, R., and Skolnick, P. (1991). Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N. Engl. J. Med. 325:473-478.
11. Basile, A.S., Pannell, L., Jaouni, T., Gammal, S.H., Fales, H.M., Jones, E.A., and Skolnick, P. (1990). Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Proc. Natl. Acad. Sci. U.S.A. 87:5263-5267.
12. Bassett, M.L., Mullen, K.D., Skolnick, P., and Jones, E.A. (1987). Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABA-A-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 93:1069-1077.
13. Bonetti, E.P., Burkard, W.P., Gabl, M., Hunkeler, W., Lorez, H.P., Martin, J.R., Mohler, H., Osterrieder, W., Pieri, L., Polc, P., Richards, J.G., Schaffener, R., Scherschlicht, R., Schoch, P., and Haefely, W.E. (1988). Ro 15-4513: Partial inverse agonism at the BZR and interaction with ethanol. Pharmacol. Biochem. Behav. 31:733-749.
14. Bosman, D.K., van den Buijs, C.A., de Haan, J.G., Maas, M.A., and Chamuleau, R.A. (1991). The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat. Gastroenterology 101:772-781.
15. 3H]muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 8:1084-1088.
16. Cadranel, J.F., el Younsi, M., Pidoux, B., Zylberberg, P., Benhamou, Y., Valla, D., and Opolon, P. (1995). Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: A double-blind pragmatic randomized, placebo study. Eur. J. Gastroenterol. Hepatol. 7:325-329.
17. Celik, T., Uzbay, T., Cinar, K., Bozkaya, H., Uzunalimoglu, O., and Yurdaydin, C. (1999). Combination treatment of hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure in the rat with benzodiazepine and opioid receptor antagonists. J. Hepatol. 31:880-886.
18. Dodd, P.R., Thomas, G.J., Harper, C.G., and Kril, J.J. (1992). Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: Effect of cirrhosis of the liver. J. Neurochem. 59:1506-1515.
19. Ferenci, P., Grimm, G., Meryn, S., and Gangl, A. (1989). Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil. Gastroenterology 96:240-243.
20. Gammal, S.H., Basile, A.S., Geller, D., Skolnick, P., and Jones, E.A. (1990). Reversal of the behavioral and electrophysiological abnormalities of an animal model of hepatic encephalopathy by benzodiazepine receptor ligands. Hepatology 11:371-378.
21. Goulenok, C., Bernard, B., Cadranel, J.F., Thabut, D., Di Martino, V., Opolon, P., and Poynard, T. (2002). Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: A meta-analysis. Aliment. Pharmacol. Ther. 16:361-372.
22. Grimm, G., Ferenci, P., Katzenschlager, R., Madl, C., Schneeweiss, B., Laggner, A.N., Lenz, K., and Gangl, A. (1988). Improvement of hepatic encephalopathy treated with flumazenil. Lancet 2:1392-1394.
23. Groeneweg, M., Gyr, K., Amrein, R., Scollo-Lavizzari, G., Williams, R., Yoo, J.Y., and Schalm, S.W. (1996). Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind, randomized, placebo-controlled multicentre trial. Electroencephalogr. Clin. Neurophysiol. 98:29-34.
24. Gyr, K., Meier, R., Haussler, J., Bouletreau, P., Fleig, W.E., Gatta, A., Holstege, A., Pomier-Layrargues, G., Schalm, S.W., Groeneweg, M., Scollo-Lavizzari, G., Ventura, E., Zeneroli, M.L., Williams, R., Yoo, Y., and Amrein, R. (1996). Evaluation of the efficacy and safety of flumazenil in the treatment of portal-systemic encephalopathy: A double blind, randomized, placebo controlled multicenter trial. Gut 39:319-324.
25. Ha, J.H., and Basile, A.S. (1996). Modulation of ligand binding to components of the GABA-A receptor complex by ammonia: Implications for the pathogenesis of hyperammonemic syndromes. Brain Res. 720:35-44.
26. Haefely, W., Kyburz, E., Gerecke, M., and Mohler, H. (1985). Recent advances in the molecular pharmacology of benzodiazepine receptors and the structure-activity relationship of their agonist and antagonists. Adv. Drug Res. 14:165-322.
27. Hazell, A.S., and Butterworth, R.F. (1999). Hepatic encephalopathy: An update of pathophysiologic mechanisms. Proc. Soc. Exp. Biol. Med. 222:99-112.
28. Hernandez-Avila, C.A., Shoemaker, W.J., and Ortega-Soto, H.A. (1998). Plasma concentrations of endogenous benzodiazepine-receptor ligands in patients with hepatic encephalopathy: A comparative study. J. Psychiatry Neurosci. 23:217-222.
29. Hunkeler, W., Mohler, H., Pieri, L., Polc, P., Bonetti, E.P., Cumin, R., Schaffner, R., and Haefely, W. (1981). Selective antagonists of benzodiazepines. Nature 290(5806):514-516.
30. Jalan, R., Turjanski, N., Taylor-Robinson, S.D., Koepp, M.J., Richardson, M.P., Wilson, J.A., Bell, J.D., and Brooks, D.J. (2000). Increased availability of central benzodiazepine receptors in patients with chronic hepatic encephalopathy and alcohol related cirrhosis. Gut 46:546-552.
31. Jones, E.A. (2003). Potential mechanisms of enhanced GABA-mediated inhibitory neurotransmission in liver failure. Neurochem. Int. 43:509-516.
32. Jones, E.A., and Basile, A.S. (1997). The involvement of ammonia with the mechanisms that enhance GABA-ergic neurotransmission in hepatic failure. In (V. Felipo and S. Grisolia, eds.), Advances in Cirrhosis, Hyperammonemia, and Hepatic Encephalopathy, Plenum, New York, pp. 75-83.
33. MacDonald, G.A., Frey, K.A., Agranoff, B.W, Minoshima, S., Koeppe, R.A., Kuhl, D.E., Shulkin, B.L., and Lucey, M.R. (1997). Cerebral benzodiazepine receptor binding in vivo in patients with recurrent hepatic encephalopathy. Hepatology 26:277-282.
34. Maddison, J.E., Dodd, P.R., Morrison, M., Johnston, G.A., and Farrell, G.C. (1987). Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy. Hepatology 7:621-628.
35. Mans, A.M., Kukulka, K.M., McAvoy, K.J., and Rokosz, N.C. (1992). Regional distribution and kinetics of three sites on the GABA-A receptor: Lack of effect of portacaval shunting. J. Cerebr. Blood Flow Metab. 12:334-346.
36. Meier, R., and Gyr, K. (1988). Treatment of hepatic encephalopathy (HE) with the benzodiazepine antagonist flumazenil: A pilot study. Eur. J. Anaesthesiol. Suppl. 2:139-146.
37. Meyer, H.P., Legemate, D.A., van den Brom, W., and 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.
38. Mullen, K.D., Szauter, K.M., and Kaminsky-Russ, K., (1990). "Endogenous" benzodiazepine activity in body fluids of patients with hepatic encephalopathy. Lancet 336:81-83.
39. Olasmaa, M., Rothstein, J.D., Guidotti, A., Weber, R.J., Paul, S.M., Spector, S., Zeneroli, M.L., Baraldi, M., and Costa, E. (1990). Endogenous benzodiazepine receptor ligands in human and animal hepatic encephalopathy. J. Neurochem. 55:2015-2033.
40. Perney, P., Butterworth, R.F., Mousseau, D.D., Lavoie, J., Fabbro-Peray, P., Blanc, F., and Pomier-Layrargues, G. (1998). Plasma and CSF benzodiazepine receptor ligand concentrations in cirrhotic patients with hepatic encephalopathy: Relationship to severity of encephalopathy and to pharmaceutical benzodiazepine intake. Metab. Brain Dis. 13:201-210.
41. Pomier-Layrargues, G., Giguère, J.F., Lavoie, J., Perney, P., Gagnon, S., D'Amour, M., Wells, J., and Butterworth, R.F. (1994). Flumazenil in cirrhotic patients in hepatic coma: A randomized double-blind placebo-controlled crossover trial. Hepatology 19:32-37.
42. Pomier-Layrargues, G., Giguere, J.F., Lavoie, J., Willems, B., and Butterworth, R.F. (1989). Pharmacokinetics of benzodiazepine antagonist Ro15-1788 in cirrhotic patients with moderate or severe liver dysfunction. Hepatology 10:969-972.
43. Püspök, A., Herneth, A., Steindl, P., and Ferenci, P. (1993). Hepatic encephalopathy in rats with thioacetamide-induced acute liver failure is not mediated by endogenous benzodiazepines. Gastroenterology 105:851-857.
44. Rossle, M., Deckert, J., and Jones, E.A. (1989). Autoradiographic analysis of GABA-benzodiazepine receptors in an animal model of acute hepatic encephalopathy. Hepatology 10:143-147.
45. Roy, S., Pomier-Layrargues, G., Butterworth, R.F., and Huet, P.M. (1988). Hepatic encephalopathy in cirrhotic and portacaval shunted dogs: Lack of changes in brain GABA uptake, brain GABA levels, brain glutamic acid decarboxylase activity and brain postsynaptic GABA receptors. Hepatology 8:845-849.
46. Samson, Y., Bernuau, J., Pappata, S., Chavoix, C., Baron, J.C., and Maziere, M.A. (1987). Cerebral uptake of benzodiazepine measured by positron emission tomography in hepatic encephalopathy. N. Engl. J. Med. 316:414-415.
47. Schafer, D.F., Fowler, J.M., Munson, P.J., Thakur, A.K., Waggoner, J.G., and Jones, E.A. (1983). Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure. J. Lab. Clin. Med. 102:870-880.
48. Schwartz-Bloom, R.D., and Sah, R. (2001). gamma-Aminobutyric acid(A) neurotransmission and cerebral ischemia. J. Neurochem. 77:353-371.
49. Scollo-Lavizzari, G., and Steinmann, E. (1985). Reversal of hepatic coma by benzodiazepine antagonist (RO 15-1788). Lancet 1:1324.
50. Steindl, P., Püspök, A., Druml, W., and Ferenci, P. (1991). Beneficial effect of pharmacological modulation of the GABA-A-benzodiazepine receptor on hepatic encephalopathy in the rat: Comparison with uremic encephalopathy. Hepatology 14:963-968.
51. van der Rijt, C.C., de Knegt, R.J., Schalm, S.W., Terpstra, O.T., and Mechelse, K. (1990). Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit. Metab. Brain Dis. 5:131-141.
52. Van der Rijt, C.C.D., Schalm S.W., Meulstree J., and Stignen, T.H. (1995). Flumazenil therapy for hepatic encephalopathy: A double-blind cross-over study. Gastroenterol. Clin. Dial. 19:572-580.
53. Venturini, I., Corsi, L., Avallone, R., Farina, F., Bedogni, G., Baraldi, C., Baraldi, M., and Zeneroli, M.L. (2001). Ammonia and endogenous benzodiazepine-like compounds in the pathogenesis of hepatic encephalopathy. Scand J. Gastroenterol. 36:423-425.
54. Widler, P., Fisch, H.U., Schoch, P., Zimmermann, A., Schlapfer, T.E., and Reichen, J. (1993). Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat. Hepatology 18:1459-1464.
55. Wildmann, J., Mohler, H, Vetter, W., Ranalder, U., Schmidt, K., and Maurer, R. (1987). Diazepam and N-desmethyldiazepam are found in rat brain and adrenal and may be of plant origin. J. Neural. Transm. 70:383-398.
56. Yurdaydin, C., Gu, Z.Q., Nowak, G., Fromm, C., Holt, A.G., and Basile, A.S. (1993). Benzodiazepine receptor ligands are elevated in an animal model of hepatic encephalopathy: Relationship between brain concentration and severity of encephalopathy. J. Pharmacol. Exp. Ther. 265:565-571.
57. Zieve, L., Ferenci, P., Rzepczynski, D., Ebner, J., and Zimmermann, C. (1987). A benzodiazepine antagonist does not alter the course of hepatic encephalopathy or neural gamma-aminobutyric acid (GABA) binding. Metab. Brain Dis. 2:201-205.