Abstract
Based on the reversal of hepatic encephalopathy in animal models with administration of specific benzodiazepine receptor antagonists, it has been postulated that this syndrome may be mediated by an endogenous benzodiazepine-like compound. In this study using a radioreceptor assay, evidence for the existence of this substance has been demonstrated in cerebrospinal fluid but not sera of rabbits with hepatic encephalopathy due to galactosamine induced hepature failure. Cerebrospinal fluid from rabbits with hepatic encephalopathy caused 36.1 ± 5.03% displacement of3H-Ro 15-1788 specific binding to cortical benzodiazepine receptors, compared to 11.7 ± 0.76% in control animals (P < 0.01). The benzodiazepine receptor binding activity has been shown to behave as a competitive inhibitor of radiolabeled benzodiazepine receptor binding. The finding of endogenous benzodiazepine binding activity affords a potential explanation for the amelioration of hepatic encephalopathy in this model with the administration of benzodiazepine receptor antagonists.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andersen, B. (1984). A proposed theory for the encephalopathies of Reye's syndrome and hepatic encephalopathy.Med. Hypoth. 15: 415–420.
Bansky, G., Meier, P. J., Ziegler, W. H., Schmid, M., and Huber, M. (1985). Reversal of hepatic coma by benzodiazepine antagonists (Ro 15-1788)Lancet 1: 1324–1325.
Bansky, G., Meier, P. J., Riederer, E., Waiser, H., Ziegler, W. H. and Schmid, M. (1987). Effect of a benzodiazepine antagonist in hepatic encephalopathy.Hepatology 7: 1103.
Baraldi, M., and Zeneroli, M. (1982). Experimental hepatic encephalopathy: Changes in the binding of γ-aminobutyric acid.Science 216: 427–429.
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.
Bassett, M. L., Müllen, K. D., Skolnick, P., and Jones, E. A. (1987). Amelioration of hepatic encephalopathy for phamacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure.Gastroenterology 93: 1069–1077.
Blitzer, B. L., Waggoner, J. G., Jones, E. A., Gralnick, H. R., Towne, D., Butler, J., Weise, V., Kopin, I. J., Walters, I., Teychenne, P. F., Goodman, D. G., and Berk, P. D. (1978). A model of fulminant hepatic failure in the rabbit.Gastroeneterology 74: 664–671.
Burke, D. A., Mitchell, K. W., Al Mardini, H., and Record, C. O. (1988). Reversal of hepatic coma with flumazenil with improvement in visual evoked potentials.Lancet 2: 505–506.
Ferenci, P., Grim, G., Meryn, S., and Gangl, A. (1989). Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil.Gastroenterology 96: 240–243.
Geddes, J. W., and Wood, J. D. (1984). Changes in the amino acid content of nerve endings (synaptosomes) induced by drugs that alter the metabolism of glutamate and γ-aminobutyric acid.J. Neurochem. 42: 16–24.
Grim, 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.
Hamon, M., and Sourbie, P. (1983). Searching for endogenous ligands of central benzodiazepine reactors.Neurochem. Int. 5: 663–672
Hartwick, R. A., Assenenza, S. P., and Brown, P. R. (1979). Identification and quantification of nucleosides, bases and other UV-absorbing compounds in serum using reversal phase high performance liquid chromatography.J. Chromatogr. 186: 647–658.
Hunkeler, W., Möhler, H., Pieri, L., Polc, P., Bonetti, E. P., Cumin, R., Schaffner, R., and Haefely, W. (1981). Selective antagonists of benzodiazepines.Nature 290: 514–516.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein measurement with the folin phenol reagent.J. Biol. Chem. 193: 265–275.
Mangano, R. M. (1986). Characterization of agonist and antagonist interactions at the benzodiazepine receptor. In O'Brien, R. A. (ed.),Receptor Binding in Drug Research, Marcel Dekker, New York, pp. 487–496.
Marangos, P. J., Trams, E., Clark-Rosenberg, R. L., Paul, S. M., and Skolnick, P. (1981). Anticonvolusant doses of inosine result in brain levels sufficient to inhibit (3H) diazepam binding.Psychopharmacology 75: 175–178.
Meier, R., and Gyr, K. (1988). Treatment of hepatic encephalopathy with the benzodiazepine antagonist flumazenil: A pilot study.Eur. J. Anesthesiol. Suppl. 2: 139–146.
Metcalf, B. W. (1979). Inhibitors of GABA metabolism.Biochem. Pharmacol. 28: 1705–1712.
Mohler, H., and Richards, J. G. (1981). Agonist and antagonist benzodiazepine receptor interaction in vitro.Nature 294: 763–765.
Mullen, K. D., Martin, J. V., Bassett, M. I., Zaharevitz, D., Mendelson, W. B., and Jones, E. A. (1986). Hepatic encephalopathy: A syndrome modulated by an endogenous benzodiazepine ligand?Hepatology 6: 1221.
Mullen, K. D., Martin, J. V., Mendelson, W. B., Bassett, M. L., and Jones, E. A. (1988). Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy?Lancet 1: 457–459.
Mullen, K. D., Szauter, K. M., Kaminsky, K., Tolentino, P. D., and McCullough, A. J. (1989). Detection and characterization of endogenous benzodiazepine activity in both animal models and humans with hepatic encephalopathy: In Butterworth, R. F., and Pomer-Layrargues, G. (eds.), Humana Press, Clifton, N.J. (in press).
Munson, P. J., and Rodbard, D. (1980). Ligand: A versatile computerized approach for characterization of ligand binding systems.Anal. Biochem. 197: 220–239.
Nielson, M., and Braestrup, C. (1980). Ethyl-β-carboline-3-carboxylate shows differential benzodiazepine receptor interaction.Nature 286: 606–607.
Schafer, D. F., and Jones, E. A. (1982). Hepatic encephalopathy and the γ-aminobutyric acid neurotransmitter system.Lancet 1: 18–19.
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.Gastroenterology 86: 540–545.
Skolnick, P., Goodwin, F. K., and Paul, S. M. (1979). A rapid and sensitive radioreceptor assay for benzodiazepine in plasma.Arch. Gen. Psych. 36: 78–80.
Skolnick, P., Paul, S. M., and Marangos, P. J. (1980). Purines as endogenous ligand for the benzodiazepine receptor.Fed. Proc. 39: 3050–3055.
Skolnick, P., Schweri, M. M., Williams, E. F., Moncada, V. Y., and Paul, S. M. (1982). An in vitro binding assay which differentiates benzodiazepine “agonists” and “antagonist.”Eur. J. Pharmacol. 78: 133–136.
Wood, P. L., Loo, P., Braunwalder, A., Yokoyama, N., and Cheney, D. L. (1984). In vitro characterization of benzodiazepine receptor agonists, antagonists, inverse agonists and agonist/antagonists.J. Pharm. Exp. Ther. 231: 572–576.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Müllen, K.D., Martin, J.V., Mendelson, W.B. et al. 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 (1989). https://doi.org/10.1007/BF00999771
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00999771