Abstract
The hypothesis that agonist ligands of the central benzodiazepine (BZ) receptor contribute to the manifestations of hepatic encephalopathy (HE) by enhancing the action of GABA was originally suggested by anecdotal observations of ameliorations of HE following administration of a BZ receptor antagonist. The term natural BZs has been introduced for BZ receptor ligands which have been demonstrated in brain, cerebrospinal fluid, and plasma of normal animals and humans and which cannot be attributed to ingestion of pharmaceutical BZs. Possible sources of natural BZs or their precursors include the food cycle and intestinal bacteria, but probably not mammalian tissues. In liver failure, mean levels of natural BZ agonist ligands are increased in both animal models and humans and correlate with the severity of HE; the levels associated with HE are sufficient to induce at least mild neuroinhibitory behavioral effects. Flumazenil is the only BZ receptor antagonist currently available for clinical use. Intravenously administered flumazenil has been shown to induce ameliorations of HE in large proportions of patients with acute or chronic liver failure. Its beneficial effects on HE are limited by its weak partial agonist properties and, because of rapid metabolism, the transience of its effects. Reports of lack of effects of flumazenil on HE may be attributable to studying inappropriate animal models and/or complex encephalopathic states rather than HE uncomplicated by other encephalopathies. Other experimental BZ receptor antagonists with partial inverse agonist properties have been reported to be more effective than flumazenil in ameliorating HE in animal models. The contribution of BZ receptor antagonists on the management of HE may be enhanced further by (1) assessing the efficacy of an oral preparation of flumazenil on chronic portal-systemic encephalopathy; (2) conducting preliminary clinical trials of the efficacy of BZ antagonists with partial inverse agonists properties on HE; and (3) developing new BZ antagonists with properties superior to those of flumazenil, such as milder partial agonist properties and slower metabolism.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Tallman JF, Paul SM, Skolnick P, Gallager DW. Receptors for the age of anxiety: the pharmacology of benzodiazepines. Science. 1980;207:274–81.
Paul SM, Marangos PJ, Skolnick P. The benzodiazepine-GABA-chloride ionophore receptor complex. Common site of minor tranquilizer action. Biol Psychiatry. 1981;16:213–29.
Anholt RR, Pedersen PL, De Souza EB, Snyder SH. The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J Biol Chem. 1986;261:576–83.
Skolnick P, Paul SM. The benzodiazepine/GABA receptor chloride channel complex. ISI Atlas Sci Pharmacol. 1988;2:19–22.
Haefely W, Kyburaz E, Gerecke M, Mohler H. Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships if their agonists and antagonists. Adv Drug Res. 1985;14:165–322.
Haefely WE, Martin JR, Richards JG, Schoch P. The multiplicity of actions of benzodiazepine receptor ligands. Can J Psychiatry. 1993;38 Suppl 4:S102.
Haefely WE. Allosteric modulation of the GABAA receptor channel: a mechanism for interaction with a multitude of central nervous system functions. In: Mohler H, De Prada M, editors. The challenge of neuropharmacology. A Tribute to the Memory of Willy Haefely. Basel: Editiones Roche; 1994. p. 15–39.
Study RE, Barker JL. Diazepam and (-)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of gamma-aminobutyric acid responses in cultured central neurones. Proc Natl Acad Sci U S A. 1981;78:7180–4.
Jones EA, Weissenborn K. Neurology and the liver. J Neurol Neurosurg Psychiatry. 1997;63:279–93.
Jones EA, Basile AS, Mullen KD, Gammal SH. Flumazenil: potential implications for hepatic encephalopathy. Pharmacol Ther. 1990;45:331–43.
Gardner CR. Pharmacological profiles in vivo of benzodiazepine receptor ligands. Drug Dev Res. 1988;12:1–28.
Jones EA. Benzodiazepine receptor ligands and hepatic encephalopathy: further unfolding of the GABA story. Hepatology. 1991;14:1286–90.
Schafer DF, Jones EA. Hepatic encephalopathy and the γ-aminobutyric acid neurotransmitter system. Lancet. 1982;1:18–20.
Schafer DF, Pappas SC, Brody LE, Jacobs R, Jones EA. Visual evoked potentials in a rabbit model of hepatic encephalopathy. I. Sequential changes and comparisons with drug-induced comas. Gastroenterology. 1984;86:540–5.
Jones DB, Mullen KD, Roessle M, Maynard T, Jones EA. Hepatic encephalopathy: application of visual evoked responses to test hypotheses of its pathogenesis in rats. J Hepatol. 1987;4:118–26.
Jones EA. Potential mechanisms of enhanced GABA-mediated inhibitory neurotransmission in liver failure. Neurochem Int. 2003;43:509–16.
Anderson B. A proposed theory for the encephalopathies of Reye’s syndrome and hepatic encephalopathy. Med Hypotheses. 1984;15:415–20.
Bansky G, Meier PJ, Zeigler WH, et al. Reversal of hepatic coma by benzodiazepine antagonist (Ro 15-1788). Lancet. 1985;1:1324–5.
Baraldi M, Zeneroli ML, Ventura E, et al. Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: reversal by a benzodiazepine antagonist. Clin Sci. 1984;67:167–75.
Scollo-Lavizzari G, Steinmann E. Reversal of hepatic coma by benzodiazepine antagonist (Ro 15-1788). Lancet. 1985;1:1324.
Mullen KD, Martin JV, Mendelson WB, Bassett ML, Jones EA. Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy? Lancet. 1988;1:457–9.
Basile AS, Jones EA, Skolnick P. The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev. 1991;43:27–71.
Mullen KD, Kaminsky-Russ K. Pathogenesis of hepatic encephalopathy: potential future approaches. Dig Dis. 1996;14 Suppl 1:20–9.
Klotz U, Ziegler G, Reiman IW. Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Clin Pharmacol. 1984;27:115–7.
Mullen KD, Martin JV, Mendelson WB, Jones EA. Further evidence that HE in the galactosamine rabbit model may be mediated by an endogenous BZ compound. In: Soeters PB, Wilson JHP, Meier AJ, Holm E, editors. Advances in ammonia metabolism and hepatic encephalopathy. Amsterdam: Elsevier Science; 1988. p. 333–7.
Mullen KD, Martin JV, Mendelson WB, Kaminsky-Russ K, Jones EA. Evidence for the presence of a benzodiazepine receptor binding substance in cerebrospinal fluid of a rabbit model of hepatic encephalopathy. Metab Brain Dis. 1989;4:253–60.
Mullen KD, Szauter KM, Kaminsky-Russ K, et al. Detection and characterization of endogenous benzodiazepine activity in both animal models and humans with hepatic encephalopathy. In: Butterworth RF, Layrargues GP, editors. Hepatic encephalopathy: pathophysiology and treatment. Clifton: Humana; 1989. p. 287–94.
Mullen KD, Szauter KM, Kaminsky-Russ K. “Endogenous” benzodiazepine activity in body fluids of patients with hepatic encephalopathy. Lancet. 1990;336:81–3.
Basile AS, Gammal SH, Jones EA, Skolnick P. The GABAA receptor complex in an experimental model of hepatic encephalopathy: evidence for elevated levels of an endogenous benzodiazepine receptor ligand. J Neurochem. 1989;53:1057–63.
Basile AS, Ostrowski NK, Gammal SH, Jones EA, The SP. The GABAA receptor complex in hepatic encephalopathy. Autoradiographic evidence for the presence of elevated levels of a benzodiazepine receptor ligand. Neuropsychopharmacology. 1990;3:61–7.
Basile AS, Pannell L, Jaouni T, et al. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Proc Natl Acad Sci. 1990;87:5263–7.
Olasmaa M, Rothstein JD, Guidotti A, et al. Endogenous benzodiazepine receptor ligands in human and animal hepatic encephalopathy. J Neurochem. 1990;55:2015–23.
Basile AS. The contribution of endogenous benzodiazepine receptor ligands to the pathogenesis of hepatic encephalopathy. Synapse. 1991;7:141–50.
Mohler H, Richards JG. Agonist and antagonist benzodiazepine receptor interactions in vitro. Nature. 1981;294:763–5.
Braestrup C, Schmiechen R, Neef G, et al. Interaction of convulsive ligands with benzodiazepine receptors. Science. 1982;216:1241–3.
Skolnick P, Schweri MM, Williams ER, et al. An in vitro binding assay which differentiates benzodiazepine “agonists” and “antagonists”. Eur J Pharmacol. 1982;78:133–6.
Olasmaa M, Guidotti A, Costa E, et al. Endogenous benzodiazepines in hepatic encephalopathy. Lancet. 1989;1:491–2.
Widler P, Fisch HU, Schoch P, et al. Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat. Hepatology. 1993;18:1459–64.
Basile AS, Jones EA. The involvement of benzodiazepine receptor ligands in hepatic encephalopathy. Hepatology. 1994;20:541–2.
Basile AS, Hughes RD, Harrison PM, et al. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J Med. 1991;325:473–8.
Mullen KD. Benzodiazepine compounds and hepatic encephalopathy. N Engl J Med. 1991;325:509–11.
Mullen KD, Roessle M, Jones DB, Grun M, Jones EA. Precipitation of overt encephalopathy in the portacaval shunted rat: towards the development of an adequate model of chronic portal-systemic encephalopathy. Eur J Gastroenterol Hepatol. 1997;9:293–8.
Yurdaydin C, Gu Z-Q, Nowak G, et al. Benzodiazepine receptor ligands are elevated in an animal model of hepatic encephalopathy: relationship between brain concentration and severity of encephalopathy. J Pharmacol Exp Ther. 1993;265:565–71.
Basile AS, Harrison PM, Hughes RD, et al. Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy. Hepatology. 1994;19:112–21.
Guidotti A, Forchetti CM, Corda MG, et al. Isolation, characterization and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors. Proc Natl Acad Sci U S A. 1983;80:3531–5.
Shoyab M, Gentry L, Marquardt H, Todaro G. Isolation and characterization of a putative endogenous benzodiazepine (endozepine) from bovine and human brain. J Biol Chem. 1986;261:1168–73.
Matquardt H, Todaro G, Shoyab M. Complete amino acid sequences of bovine and human endozepines. J Biol Chem. 1986;262:9227–31.
Gray PW. Molecular biology of diazepam binding inhibitor. Neuropharmacology. 1987;26:863–6.
Rothstein JD, McKhann G, Guarneri P, et al. Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy. Ann Neurol. 1989;26:57–62.
Mullen KD, Szauter KM, Kaminsky-Russ K, et al. Detection and characterization of endogenous benzodiazepine activity in both animal models and humans with hepatic encephalopathy. In: Butterworth RF, Layrargues GP, editors. Hepatic encephalopathy: pathophysiology and treatment. Clifton: Humana; 1989. p. 287–94.
de Blas AL, Park D, Friedrich P. Endogenous benzodiazepine-like molecules in the human, rat and bovine brains studied with a monoclonal antibody to benzodiazepines. Brain Res. 1987;413:275–84.
Baraldi M, Avallone R, Corsi L, Venturini I, Baraldi C, Zeneroli ML. Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy. Metab Brain Dis. 2009;24:81–93.
Medina JH, Pena C, Piva M, et al. Presence of benzodiazepine-like molecules in mammalian brain and milk. Biochem Biophys Res Commun. 1988;152:534–9.
Unseld E, Krishna DR, Fischer C, Klotz U. Detection of desmethyldiazepam and diazepam in brain of different species and plants. Biochem Pharmacol. 1989;38:2473–8.
Wildmann J, Vetter W, Ranalder UB, et al. Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato. Biochem Pharmacol. 1988;37:3549–59.
Wildmann J. Increase in neural benzodiazepines in wheat and potato during germination. Biochem Biophys Res Commun. 1988;157:1436–43.
Yurdaydin C, Walsh TJ, Engler HD, et al. Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res. 1995;679:42–8.
Sangameswaran L, Fales HM, Friedrich P, DeBlas A. Purification of a benzodiazepine from bovine brain and detection of benzodiazepine-like immunoreactivity in human brain. Proc Natl Acad Sci U S A. 1986;83:9236–40.
Wildmann J, Niemann J, Matthaei H. Endogenous benzodiazepine receptor agonist in human and mammalian plasma. J Neural Transm. 1986;66:151–60.
Wildmann J, Ranalder U. Presence of lorazepam in the blood plasma of drug free rats. Life Sci. 1988;43:1257–60.
Unseld E, Fischer C, Rothemund E, Klotz U. Occurrence of “natural” diazepam in human brain. Biochem Pharmacol. 1990;39:210–2.
Luckner M. Secondary metabolism in microorganisms, plants and animals. Berlin: Springer; 1984. p. 274.
Haefely W. The preclinical pharmacology of Flumazenil. Eur J Anaesthesiol Suppl. 1988;2:25–36.
Basile AS, Gammal SH, Mullen KD, Jones EA, Skolnick P. Differential responsiveness of cerebellar Purkinje neurons to GABA and benzodiazepine receptor ligands in a animal model of hepatic encephalopathy. J Neurosci. 1988;8:2414–21.
Jones EA, Skolnick P. Benzodiazepine receptor ligands and the syndrome of hepatic encephalopathy. In: Popper H, Schaffner F, editors. Progress in liver diseases, vol. IX. Philadelphia: WB Saunders; 1990. p. 345–70.
Pomier-Layrargues G, Giguere J-F, Lavoie J, et al. Pharmacokinetics of benzodiazepine antagonist Ro 15-1788 in cirrhotic patients with moderate and severe liver dysfunction. Hepatology. 1989;10:969–72.
Samson Y, Hantraye P, Baron JC, et al. Kinetics and displacement of [11 C]Ro 15-1788, a benzodiazepine antagonist, studied in human brain in vivo by positron tomography. Eur J Pharmacol. 1985;110:247–51.
Samson Y, Bernuau J, Pappata S, Chavoix C, Baron JC, Maziere MA. Cerebral uptake of benzodiazepine measured by positron emission tomography in hepatic encephalopathy. N Engl J Med. 1987;316:414–5.
Savic I, Widen L, Stone-Elander S. Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet. 1991;337:133–7.
File SE, Pellow S. Intrinsic actions of benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology. 1986;88:1–11.
Scollo-Lavizzari G. The anticonvulsant effect of the benzodiazepine antagonist, Ro 15-1788: an EEG study in 4 cases. Eur Neurol. 1984;23:1–6.
Grimm G, Ferenci P, Katzenschlager R, et al. Improvement of hepatic encephalopathy treated with flumazenil. Lancet. 1988;2:1392–4.
Bansky G, Meier PJ, Riederer E, et al. Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology. 1989;97:744–50.
Jones EA, Ferenci P. Hepatic encephalopathy, GABAergic neurotransmission and the benzodiazepines. In: Conn HO, Bircher J, editors. Hepatic encephalopathy: syndromes and therapies. Bloomington: Medi-Ed Press; 1994. p. 75–100.
Burke DA, Mitchel KW, Burke DA, Mitchel KW, Al Mardini H, et al. Reversal of hepatic coma with flumazenil with improvement in visual evoked potentials. Lancet. 1988;1:505–6.
Googay R, Hayes PC, Bzeizi K, O’Carroll RE. Benzodiazepine receptor antagonism improves reaction time in latent hepatic encephalopathy. Psychopharmacology. 1995;119:295–8.
Jones EA, Giger-Mateeva VI, Reits D, et al. Visual event-related potentials in cirrhotic patients without overt encephalopathy: the effects of flumazenil. Metab Brain Dis. 2001;16:43–53.
Ferenci P, Grimm G, Meryn S, Gangl A. Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine receptor antagonist flumazenil. Gastroenterology. 1989;96:240–3.
Bassett ML, Mullen KD, Skolnick P, Jones EA. Amelioration of hepatic encephalopathy by pharmacological antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology. 1987;93:1069–77.
Gammal SH, Basile AS, Geller D, Skolnick P, Jones EA. Reversal of the behavioral and electrophysiological abnormalities of an animal model of hepatic encephalopathy by benzodiazepine receptor ligands. Hepatology. 1990;11:371–78.
Van der Rijt CCD, de Knegt RJ, Schalm SW, et al. Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit. Metab Brain Dis. 1990;5:131–41.
Bosman DK, van den Buijs CACG, de Haan JG, Maas MAW, Chamuleau RAFM. The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat. Gastroenterology. 1991;101:772–81.
Steindl P, Puspok A, Druml W, Ferenci P. Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: comparison with uremic encephalopathy. Hepatology. 1991;14:963–8.
Puspok A, Herneth A, Steindl P, Ferenci P. Hepatic encephalopathy in rats with thioacetamide-induced acute liver failure is not mediated by endogenous benzodiazepines. Gastroenterology. 1993;105:851–7.
Maher HP, Legemate DA, van den Brom W, Rothuizen J. Improvement of chronic hepatic encephalopathy in dogs by the benzodiazepine-receptor partial inverse agonist sarmazenil, but not by the antagonist flumazenil. Metab Brain Res. 1998;13:241–51.
Mullen KD, Basile AS. Benzodiazepine receptor antagonists and hepatic encephalopathy: where do we stand? Gastroenterology. 1993;105:937–40.
Zieve L, Ferenci P, Rzepczynski D, Ebner J, Zimmermann Ch. A benzodiazepine antagonist does not alter the course of hepatic encephalopathy or neural gamma-aminobutyric acid (GABA) binding. Metab Brain Dis. 1987;2:201–5.
Jones EA. Hepatocellular failure. In: Warrell DA, Cox TM, Firth JD, editors. Oxford textbook of medicine. 5th ed. Oxford: Oxford University Press; 2010. p. 2493–505.
Blitzer BL, Waggoner JG, Jones EA, et al. A model of fulminant hepatic failure in the rabbit. Gastroenterology. 1978;74:664–71.
Mullen KD, Schafer DF, Cuchi P, et al. Evaluation of the suitability of galactosamine-induce fulminant hepatic failure as a model of hepatic encephalopathy in the rat and rabbit. In: Soeters PB, Wilson JMP, Meijer AJ, Holm E, editors. Recent advances in ammonia metabolism and hepatic encephalopathy. Amsterdam: Elsevier; 1988. p. 205–12.
Als-Nielsen B, Gluud LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database Syst Rev. 2004;(2):CD002798.
Schafer DF. In hepatic coma, the problem comes from the colon, but will the answer come from there? J Lab Clin Med. 1987;110:253–4.
Schafer DF. Hepatic coma: studies on the target organ. Gastroenterology. 1987;93:1131–4.
Jones EA, Yurdaydin C, Basile AS. Benzodiazepine antagonists and the management of hepatic encephalopathy. In: Capacaccia L, Merli M, Riggio O, editors. Advances in hepatic encephalopathy and metabolic nitrogen exchange. Boca Raton: CRC Press; 1995. p. 549–63.
Sutherland LR, Minuk GY. Ro 15-1788 and hepatic failure. Ann Intern Med. 1988;108:158.
Ferenci P, Herneth A, Steindl P. Newer approaches to therapy of hepatic encephalopathy. In: Blei AT, Butterworth RF (Eds). Hepatic encephalopathy. Semin Liver Dis. 1996;16:329–38.
Van der Rijt CCD, Schalm SW, Meulster J, Stijnen T. Flumazenil therapy for hepatic encephalopathy: a double-blind cross-over study. Hepatology. 1989;10:590.
Klotz U, Walker S. Flumazenil and hepatic encephalopathy. Lancet. 1989;1:155–6.
Ahboucha S, Coyne L, Hirakawa R, Butterworth RF, Halliwell RF. An interaction between benzodiazepines and neuroactive steroids at GABAA receptors in cultured hippocampal neurons. Neurochem Int. 2006;48:703–7.
Bassett ML, Mullen KD, Scholz B, et al. Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy. Gastroenterology. 1990;98:747–57.
Albrecht J, Jones EA. Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J Neurolog Sci. 1999;170:138–46.
Gammal SH, Basile AS, Skolnick P, Jones EA. Isolated CNS neurons from a model of hepatic encephalopathy exhibit increased sensitivity to a benzodiazepine. In: Butterworth RF, Pomier Layrarques G, editors. Hepatic encephalopathy: pathophysiology and treatment. Clifton: Humana; 1989. p. 295–304.
Bakti G, Fisch HU, Karlaganis G, Minder C, Bircher J. Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology. 1987;7:629–38.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
This is one of the last publications of E. Anthony Jones who died unexpectedly on January 23rd 2012. His memory will live-on in his many proteges (K.D. Mullen).
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Jones, E.A., Mullen, K.D. (2012). The Role of Natural Benzodiazepines Receptor Ligands in Hepatic Encephalopathy. In: Mullen, K., Prakash, R. (eds) Hepatic Encephalopathy. Clinical Gastroenterology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-836-8_6
Download citation
DOI: https://doi.org/10.1007/978-1-61779-836-8_6
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-61779-835-1
Online ISBN: 978-1-61779-836-8
eBook Packages: MedicineMedicine (R0)