Abstract
The functional activity of the gamma-aminobutyric acid (GABAA) receptor-chloride ionophore complex was studied in rats with hepatic encephalopathy (HE) secondary to thioacetamide-induced fulminant hepatic failure (FHF). Muscimol stimulation and benzodiazepine potentiation of GABA receptor-mediated36Cl− uptake into cerebral cortical synaptoneurosomes was compared in HE and control rats. [3H]Flumazenil binding assays were conducted to determine whether the levels of endogenous benzodiazepine-like ligands in extracts of cortex were increased with stages of encephalopathy in this animal model of HE. In both control and HE rats maximal uptake of36Cl− via the GABAA receptor complex occurred at muscimol concentrations of 30μM. Potentiation of muscimol-stimulated36Cl− uptake into synaptoneurosomes by diazepam (5μM) was equivalent in both groups. Aqueous extracts of proteolytically digested homogenates of cerebral cortices prepared from control and HE rats were effective in stimulating36Cl− uptake into synaptoneurosomes. Alkaline organic extracts of proteolytically digested homogenates of cerebral cortices from HE rats were more effective than corresponding extracts from controls at inhibiting the binding of [3H]flumazenil. Inhibition of [3H] fumazenil binding by organic extracts derived from the cerebral cortices of HE rats did not increase with progression of encephalopathy. The results show that muscimol-stimulated36Cl− uptake into synaptoneurosomes and, consequently, GABAA receptor-mediated chloride channel function are not significantly altered in the model of HE studied and are consistent with the hypothesis that HE results in an increased availability of one or more endogenous ligands which can augment GABA receptor-gated chloride conductance.
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References
Baktir, G., Fisch, H. V., Kariaganis, G., Minder, C., and Bircher, J. (1987). Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: Model experiments with triazolam.Hepatology 9: 629–638.
Baraldi, M., and Zeneroli, M. L. (1982). Experimental hepatic encephalopathy: Changes in the binding of gamma aminobutyric acid.Science 216: 427–429.
Baraldi, M., Zeneroli, M. L., Ventura, E., Penne, A., Pinelli, G., Ricci, P., and Santi, M. (1984a). Portal-systemic encephalopathy in dogs: Changes in brain GABA receptors and neurochemical correlates. In Kleinberger, G., Ferenci, P., Riederer, P., and Thaler, H. (eds.),Advances in Hepatic Encephalopathy and Urea Cycle Diseases, Karger, Basel, pp. 353–359.
Baraldi, M., Zeneroli, M. L., Ventura, E., Penne, A., Pinelli, G., Ricci, P., and Santi, M. (1984b). 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.
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.
Basile, A. S., Gammal, S. H., Jones, E. A., and Skolnick, P. (1989). GABA receptor complex in an experimental model of hepatic encephalopathy: Evidence for elevated levels of an endogenous benzodiazepine receptor ligand.J. Neurochem. 53: 1057–1063.
Basile, A. S., Ostrowski, N. L., Gammal, S. H., Jones, E. A., and Skolnick, P. (1990). The GABAA receptor complex in hepatic encephalopathy: Autoradiographic evidence for the presence of elevated levels of a benzodiazepine receptor ligand.Psychoneuropharmacology 61: 61–71.
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.
Bassett, M. L., Mullen, K. D., Scholz, B., Fenstermacher, J. D., and Jones, E. A. (1990). Increased brain uptake of γ-aminobutyric acid in a rabbit model of hepatic encephalopathy.Gastroeterology 98: 747–757.
Branch, R. A., Morgan, M. H., Jones, J., and Read, A. E. (1976). Intravenous administration of diazepam in patients with chronic liver disease.Gut 17: 975–983.
Ferreira, M. R., Gammal, S. H., and Jones, E. A. (1988). Hepatic encephalopathy (HE): Evidence of increased GABA-mediated neurotransmission in a rat model of fulminant hepatic failure (FHF).Gastroenterology 94: A616.
Gammal, S. H., Jones, E. A., Bassett, M. L., Mullen, K. D., Geller, D., and Skolnick, P. (1988). Antagonists of the GABA/benzodiazepine receptor complex ameliorate hepatic encephalopathy in two models of fulminant hepatic failure. In Soeters, P. B., Wilson, J. H. P., Meijer, A. J., and Holm, E. (eds.),Advances in Ammonia Metabolism and Hepatic Encephalopathy, Excerpta Medica, Amsterdam, pp. 325–332.
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.
Hollingsworth, E. B., McNeal, I. T., Burton, J. L., Williams, R. J., Daly, T. W., and Creuling, C. R. (1985). Biochemical character of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3′,5′-monophosphate-generating systems, receptors, enzymes.J. Neurosci. 5: 2240–2253.
Jones, D. B., Mullen, K. D., Roessle, M., Maynard, T., 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.
Jones, E. A., Gammal, S. H., and Martin, P. (1988). Hepatic encephalopathy: New light on an old problem.Q. J. Med. New Ser. 69: 851–867.
Jones, E. A., Skolnick, P., Gammal, S. H., Basile, A. S., and Mullen, K. D. (1989). The gamma aminobutyric acid A (GABAA) receptor complex and hepatic encephalopathy: Some recent advances.Ann. Intern. Med. 110: 532–546.
Khandelwal, J. K., Prell, G. D., Morrishow, A. M., and Green, J. P. (1989). Presence and measurement of imidazole acetic acid, a gamma aminobutyric acid agonist in rat brain and human cerebrospinal fluid.J. Neurochem. 52: 1107–1113.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein determination with the Folin phenol reagent.Biol. Chem. 193: 265–275.
Morrow, A. L., and Paul, S. M. (1988). Benzodiazepine enhancement of gamma-aminobutyric acidmediated chloride ion flux in rat brain synaptoneurosomes.J. Neurochem. 50: 302–306.
Mullen, K. D., Szauter, K. M., Kaminsky, K., Tolentino, P. D., and McCullough, A. J. (1990). Detection and characterization of endogenous benzodiazepine activity in both animal models and humans with hepatic encephalopathy. In Butterworth, R. F., and Lagrargues, G. P. (eds.),Hepatic Encephalopathy, Pathophysiology and Treatment, Humana Press, Clifton, N.J., pp. 287–294.
Osselton, M. D. (1977). The release of basic drugs by the enzymic digestion of tissue in cases of poisoning.J. Forens. Sci. Soc. 17: 189–194.
Pappas, S. C. (1984). Increased γ-aminobutyric acid (GABA) receptors in the brain precedes hepatic encephalopathy (HE) in fulminant hepatic failure (FHF).Hepatology 4: 1051.
Pappas, S. C., and Gordon, V. P. (1986). Altered brain GABA binding and synaptic plasma membrane (SPM) in cirrhosis: A role in the pathogenesis of chronic hepatic encephalopathy?Hepatology 6: 1106.
Pappas, S. C., Ferenci, P., and Jones, E. A. (1984). Hepatic encephalopathy: A disorder of plasma membrane composition and fluidity? In Kleinberger, G., Ferenci, P., Riederer, P., and Thaler, H.. (eds.),Advances in Hepatic Encephalopathy and Urea Cycle Diseases, Karger, Basel, pp. 331–336.
Paul, S. M., Marangos, P. J., and Skolnick, P. (1981). The benzodiazepine-GABA-chloride ionophore receptor complex: Common site of minor tranquilizer action.Biol. Psychiat. 16: 213–229.
Rossle, M., Winstanley, F. P., Haag, K., Mullen, K. D., and Jones, E. A. (1990). Synaptic membrane complex carbohydrates in experimental hepatic encephalopathy.Metab. Brain Dis. 5: 119–129.
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.
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.
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Baker, B.L., Morrow, A.L., Vergalla, J. et al. Gamma-aminobutyric acid (GABAA) receptor-function in a rat model of hepatic encephalopathy. Metab Brain Dis 5, 185–193 (1990). https://doi.org/10.1007/BF00997072
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DOI: https://doi.org/10.1007/BF00997072