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Improvement of Chronic Hepatic Encephalopathy in Dogs by the Benzodiazepine-Receptor Partial Inverse Agonist Sarmazenil, but Not by the Antagonist Flumazenil

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Abstract

Therapeutic modulation of the increased GABAergic tone in chronic hepatic encephalopathy (HE) by the benzodiazepine receptor (BR) antagonist flumazenil (F) has led to conflicting results in humans and animal models for HE. The BR inverse agonist sarmazenil (S) has only been used in animal models of acute HE. Therefore we investigated the effects of intravenous injection of F and S in dogs with chronic HE 8 to 12 weeks after placement of a portocaval shunt and 40% hepatectomy (n=7), compared to sham-operated pair-fed controls (n=7). The HE dogs had hyperammonemia (298±48 μM v 33±3 before surgery (mean±SEM)) and signs of HE at the start of the experiments (0.9±0.1 (scale 0-4)). Three (S3) and 8 (S8) mg/kg of S resulted in a significant improvement of encephalopathy (grade 0.9±0.2 immediately before v 0.5±0.1 after injection (S3) and 0.7±0.1 v 0.3±0.1 (S8)) and increase in mean dominant frequency of the EEC (MDF; 9.1±0.7 Hz v 11.1±0.3 (S3) and 8.9±0.5 v 11.0±0.3 (S8)) in HE dogs, whereas 15 mg/kg of S, 3 and 8 mg/kg of F, and the vehicle had no significant effects. The efficacy of S in these dogs is consistent with an increased GABAergic tone in the pathogenesis of chronic HE. The lack of effects of F makes a role for endogenous benzodiazepines herein unlikely.

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REFERENCES

  • Amodio P., Quero J.C., del Piccolo F., Gatta A., and Schalm S.W. (1996). Diagnostic tools for the detection of subclinical hepatic encephalopathy: Comparison of standard and computerized psychometric tests with spectral-EEG. Metab. Brain Dis. 11:315–327.

    PubMed  Google Scholar 

  • Amodio P., Marchetti P., del Piccolo F., Beghi A., Comacchio F., Carraro P. et al. (1997). The effect of flumazenil on subclinical psychometric or neurophysiological alterations in cirrhotic patients: A double-blind placebo-controlled study. Clin. Physiol. 17:533–539.

    Article  PubMed  Google Scholar 

  • Bansky G., Meier P.J., Ziegler W.H., Walser H., Schmid M., and Huber M. (1985). Reversal of hepatic coma by benzodiazepine antagonist Ro15-1788. Lancet i:1324–1325.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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. USA 87:5263–5267.

    PubMed  Google Scholar 

  • Basile A.S. (1991). The contribution of endogenous benzodiazepine receptor ligands to the pathogenesis of hepatic encephalopathy. Synapse 7:141–150.

    PubMed  Google Scholar 

  • Basile A.S., Hughes R.D., Harrison P.M., Murata Y., Pannell L., Jones E.A. et al. (1991a). Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N. Engl. J. Med. 325:473–478.

    Google Scholar 

  • Basile A.S., Jones E.A., and Skolnick P. (1991b). The pathogenesis and treatment of hepatic encephalopathy. Evidence for the involvement of benzodiazepine receptor ligands. Pharmacol. Rev. 43:27–71.

    PubMed  Google Scholar 

  • Basile A.S. and Jones E.A. (1994). The involvement of benzodiazepine receptor ligands in hepatic encephalopahy. Hepatology 20:541–542.

    Article  PubMed  Google Scholar 

  • Basile A.S. and Jones E.A. (1997). Ammonia and GABAergic neurotransmission: Interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology 25:103–105.

    Article  PubMed  Google Scholar 

  • Bassett M.L., Mullen K.D., Skolnick P., and Jones E.A. (1987). Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA/benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 93:1069–1077.

    PubMed  Google Scholar 

  • Bitran D., Hilvers R.J., and Kellogg C.K. (1991). Anxiolytic effects of 3a-Hydroxy-5a[ß]pregnan-20-one — endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res. 561:157–161.

    Article  PubMed  Google Scholar 

  • Bosman D.K., van den Buijs C.A.C.G., de Haan J.G., Maas M.A.W., and Chamuleau R.A.F.M. (1991). The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat. Gastroenterology 101:772–781.

    PubMed  Google Scholar 

  • Butterworth R.F., Lavoie J., Giguere J.F., and Pomier-Layrargues G. (1988). Affinities and densities of high-affinity 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.

    PubMed  Google Scholar 

  • Butterworth R.F. (1996). Neuroactive amino acids in hepatic encephalopathy. Metab. Brain Dis. 11:165–173.

    PubMed  Google Scholar 

  • Conn H.O. (1988). The hepatic encephalopathies. In (H.O. Conn, and J. Bircher, eds.) Hepatic Encephalopathy: Management with Lactulose and Related Carbohydrates. Medi-Ed Press, East Lansing, Michigan, pp. 3–14.

    Google Scholar 

  • Costa E. (1991). The allosteric modulation of GABA-A receptors. Seventeen years of research. Neuropsychopharmacology 4:225–235.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Gooday R., Hayes P.C., Bzeizi K., and O'Carroll R.E. (1995). Benzodiazepine receptor antagonism improves reaction time in latent hepatic encephalopathy. Psychopharmacology 119:295–298.

    PubMed  Google Scholar 

  • 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, randomised, placebo-controlled multicentre trial. Electroencephalogr. Clin. Neurophysiol. 98:29–34.

    Article  PubMed  Google Scholar 

  • Gyr K., Meier R., Haussler J., Bouletreau P., Fleig W.E., Gatta A. et al. (1996). Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: A double blind, randomised, placebo controlled multicentre study. Gut 39:319–324.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Haefely W.E. (1990). The GABAA-benzodiazepine receptor: Biology and pharmacology. Neurobiol. Anx. 3:165–188.

    Google Scholar 

  • Jones D.B., Mullen K.D., Rössle M., and Jones E.A. (1987). Hepatic encephalopathy: Application of visual evoked responses to test hypotheses of its pathogenesis in rats. J. Hepatol. 4:118–126.

    PubMed  Google Scholar 

  • Jones E.A. (1991). Benzodiazepine receptor ligands and hepatic encephalopathy: Further unfolding of the GABA story. Hepatology 14:1286–1290.

    Article  PubMed  Google Scholar 

  • Jones E.A. and Weissenborn K. (1997). Neurology and the liver. J. Neurol. Neurosurg. Psychiatr. 63:279–293.

    PubMed  Google Scholar 

  • Maddison J.E., Yau D., Steward P., and Farrell G.C. (1986). Cerebrospinal fluid gamma-aminobutyric acid level in dogs with chronic portosystemic encephalopathy. Clin. Sci. 71:749–753.

    PubMed  Google Scholar 

  • Maddison J.E., Dodd P.R., Johnston G.A., and Farrell G.C. (1987a). Brain gamma-aminobutyric acid receptor binding is normal in rats with thioacetamide-induced hepatic encephalopathy despite elevated plasma gamma-aminobutyric acid-like activity. Gastroenterology 93:1062–1068.

    PubMed  Google Scholar 

  • Maddison J.E., Dodd P.R., Morrison M., Johnston G.A.R., and Farrell G.C. (1987b). Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy. Hepatology 7:621–628.

    PubMed  Google Scholar 

  • Maddison J.E., Watson W.E.J., and Johnston G.A.R. (1995). L-glutamate and gamma-aminobutyric acid uptake in synaptosomes from the cerebral cortex of dogs with congenital chronic hepatic encephalopathy. Metab. Brain Dis. 10:135–141.

    PubMed  Google Scholar 

  • McArdle P., Penning D.H., Dexter F., and Reynolds J.D. (1996). Flumazenil does not affect the increase in rat hippocampal extracellular glutamate concentration produced during thioacetamide-induced hepatic encephalopathy. Metab. Brain Dis. 11:329–342.

    PubMed  Google Scholar 

  • Meyer H.P., Legemate D.A., How K.L., van den Brom W.E., Voorhout G., Chamuleau R.A.F.M. et al. (1998). End-to-side portocaval anastomosis and partial hepatectomy in the dog as a model for chronic hepatic encephalopathy. J. Hepatol. 1998 (submitted)

  • Michalak A., Rose C., Butterworth J., and Butterworth R.F. (1996). Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24:908–913.

    Article  PubMed  Google Scholar 

  • Mullen K.D., Martin J.V., Mendelson W.B., Kaminsky-Russ K., and Jones E.A. (1989). Evidence for the presence of a benzodiazepine receptor binding substance in cerebrospinal fluid of a rabbit model of hepatic encephalopathy. Metab. Brain Dis. 4:253–260.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Norenberg M.D. (1996). Astrocyte-ammonia interactions in hepatic encephalopathy. Semin. Liver Dis. 16:245–253.

    PubMed  Google Scholar 

  • Polc P. (1995). Involvement of endogenous benzodiazepine receptor ligands in brain disorders: Therapeutic potential for benzodiazepine antagonists? Med. Hypoth. 44:439–446.

    Article  Google Scholar 

  • Pomier Layrargues G., Giguere J.F., Lavoie J., Perney P., Gagnon S., Damour M. et al. (1994). Flumazenil in cirrhotic patients in hepatic coma: A randomized double-blind placebo-controlled crossover trial. Hepatology 19:32–37.

    Article  PubMed  Google Scholar 

  • Popken R.J., Kropveld D., Oosting J., and Chamuleau R.A. (1983). Quantitative analysis of EEG power spectra in experimental hepatic encephalopathy. Neuropsychobiology 9:235–243.

    PubMed  Google Scholar 

  • Rothuizen J., de Kok Y., Slob A., and Mol J.A. (1996). GABAergic inhibition of the pituitary release of adrenocorticotropin and α-melanotropin is impaired in dogs with hepatic encephalopathy. Domest. Anim. Endocrinol. 13:59–68.

    Article  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Schafer D.F., and Jones E.A. (1982). Hepatic encephalopathy and the gamma-aminobutyric acid neurotransmitter system. Lancet i:18–20.

    Article  Google Scholar 

  • Schafer D.F., Pappas S.C., Brody L.E., Jacobs R., and Jones E.A. (1984). Visual evoked potentials in a rabbit model of hepatic encephalopathy. I. Sequential changes and comparisons with drug-induced comas. Gastroenterology 86:540–545.

    PubMed  Google Scholar 

  • Steindl P., Püspök A., Druml W., and Ferenci P. (1991). Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: Comparison with uremic encephalopathy. Hepatology 4:963–968.

    Article  Google Scholar 

  • Teschemacher A., Kasparov S., Kravitz E.A., and Rahamimoff R. (1997). Presynaptic action of the neurosteroid pregnenolone sulfate on inhibitory transmitter release in cultured hippocampal neurons. Brain Res. 772:226–232.

    Article  PubMed  Google Scholar 

  • van der Rijt C.C.D., and Schalm S.W. (1992). Quantitative EEG analysis and evoked potentials to measure (latent) hepatic encephalopathy. J. Hepatol. 14:141–142.

    PubMed  Google Scholar 

  • van der Rijt C.C.D., Schalm S.W., Meulstee J., and Stijnen T. (1995). Flumazenil therapy for hepatic encephalopathy. A double-blind cross over study. Gastroenterol. Clin. Biol. 19:572–580.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Wieland H.A., and Luddens H. (1994). Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor. J. Med. Chem. 37:4576–4580.

    PubMed  Google Scholar 

  • Wildmann J., Moehler 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Yurdaydin C., Walsh T.J., Engler H.D., Ha J.H., Li Y., Jones E.A., and Basile A.S. (1995). Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res. 679:42–48.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands

    Hein P. Meyer, Walter van den Brom & Jan Rothuizen

  2. Department of Surgery, Academical Medical Centre, University of Amsterdam, the Netherlands

    Dink A. Legemate

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  1. Hein P. Meyer
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  2. Dink A. Legemate
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Meyer, H.P., Legemate, D.A., van den Brom, W. et al. 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 (1998). https://doi.org/10.1023/A:1023228126315

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