Skip to main content
Log in

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit

  • Original Contribution
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were prepared from brain cortex, hippocampus and striatum. Hepatic encephalopathy was induced by a two-stage liver devascularization procedure and acute hyperammonemia by a prolonged ammonium-acetate infusion; rabbits receiving a sodium-potassium-acetate infusion served as controls. In these animal models extracellular brain glutamate levels are known to be elevated. However no significant alterations in the number nor the affinity of the MK-801 binding sites of the NMDA receptors were found during acute liver failure and acute hyperammonemia. These findings suggest that the NMDA receptor population remains unaltered in experimental encephalopathy from acute liver failure and acute hyperammonemia, despite alterations in extracellular brain glutamate levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

NMDA:

N-methyl-D-aspartate

NH4Ac:

ammoniumacetate

NaKAc:

sodium/potassium-acetate

AMPA:

amino-3-hydroxy-5-methylisoxazole4-propionic acid

References

  • Amador M. and Dani J.A. (1991) MK-801 inhibition of nicotinic acetylcholine receptor channels.Synapse 7: 207–215.

    Google Scholar 

  • Bircher J., Haemmerli U.P. and Scollo-Lavizzari G. (1971) Treatment of chronic portal-systemic encephalopathy with lactulose. Report of six patients and review of the literature.Am. J. Med. 51: 148–159.

    Google Scholar 

  • Bosman D.K., Deutz N.E.P., DeGraaf A.A., Vande Hulst R.W.N., Van Eijk H.M.H., Bovee W.M.M.J., Maas M.A.W., Jörning G.G.A. and Chamuleau R.A.F.M. (1990) Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative1H-NMR spectroscopy and biochemical investigation.Hepatology 12: 281–290.

    Google Scholar 

  • Bradford M.M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye-binding. Anal. Biochem.72: 248–254.

    Google Scholar 

  • Callachan M., Halliwell R.F., Hather N.Y., Lambert J. J. and Peters J.A. (1988) The specificity of action of MK-801. fir.J. Pharmacol. 93: 155P.

  • Collins R.C., Dobkin B.H. and Choi D.W. (1989) Selective vulnerability of the brain: new insights into the pathophysiology of stroke.Ann. Intern. Med. 110: 992–1000.

    Google Scholar 

  • Cooper A.J.L. and Plum F. (1987) Biochemistry and physiology of brain ammonia.Physiol. Rev. 67: 440–519.

    Google Scholar 

  • Da Fonseca-Wolheim F. (1973) Direkte plasma ammonia bestimmung ohne enteiweissung.Z. Klin. Chem. Klin. Biochem. 11: 426–431.

    Google Scholar 

  • DeKnegt R.J., Schalm S.W., Vander Rijt C.C.D., Fekkes D., Dalm E. and Hekking-Weijmal. (1993a) Extracellular brain glutamate during acute liver failure and during acute hyperammonemia simulating acute liver failure. An experimental study based on invivo brain dialysis.J. Hepatol. Accepted for publication.

  • De Knegt R.J., Groeneweg M., Schalm S.W. and Hekking-Weijma I. (1993b) Encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. A clinical and biochemical study.Liver. Accepted for publication.

  • Engelsen B. (1986) Neurotransmitter glutamate: its clinical importance.Acta Neural. Scan. 74: 337–355.

    Google Scholar 

  • Fagg G.E. and Massieu L. (1991) Excitatory amino acid receptor subtypes, in Excitatory amino acid antagonists. (Meldrum B.S., Ed.), pp 39–63, Blackwell Scientific Publications, London.

    Google Scholar 

  • Ferenci P., Pappas S.C., Munson P.J., and Jones E.A. (1984a) Changes in glutamate receptors on synaptic membranes associated with hepatic encephalopathy or hyperammonemia in the rabbit.Hepatology 4: 25–29.

    Google Scholar 

  • Ferenci P., Pappas S.C., Munson P.J., Henson K., Jones E.A. (1984b) Changes in the status of neurotransmitter receptors in a rabbit model of hepatic encephalopathy.Hepatology 4:186–191.

    Google Scholar 

  • Fick T.E., Schalm S.W., and De Vlieger M. (1987) A surgical model of fulminant hepatic failure in the rabbit: different effects of end-to-side versus small-diameter side-to-side portacaval shunt.Eur. Surg. Res. 19: 276–282.

    Google Scholar 

  • Fick T.E., Schalm S.W., and De Vlieger M. (1989) Continuous intravenous ammonia infusion as a model for the study of hepatic encephalopathy in rabbits.J. Surg. Res. 46: 221–225.

    Google Scholar 

  • Fonnum F. (1984) Glutamate: a neurotransmitter in mammalian brain.J. Neurochem. 42:1–11.

    Google Scholar 

  • Hamberger A. and Nystrom B. (1984) Extra- and intracellular amino acids in the hippocampus during development of hepatic encephalopathy.Neurochem. Res. 9: 1181–1192.

    Google Scholar 

  • Hindfelt B., Plum F., and Duffy T.E. (1977) Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts.J. Clin. Invest. 59: 386–396.

    Google Scholar 

  • Kavanaugh M.P., Tester B.A.C. and Weber E. (1989) Interaction of MK-801 with the nicotinic acetylcholine receptor-associated ion channel from elecroplax.Eur. J. Pharmacol. 164: 397–398.

    Google Scholar 

  • Kloog Y., Nadler V. and Sokolovsky M. (1988) Mode of binding of [3H]dibenzocycloalkenimine (MK-801) to the N-methyl-D-aspartate (NMDA) receptor and its therapeutic implication.FEBS letters 230: 167–170.

    Google Scholar 

  • Komhuber J., Mack-Burhardt F., Komhuber M.E., and Riederer P. (1989a) [3H]MK-801 binding sites in post-mortem human frontal cortex.Eur. J. Pharmacol. 162: 483–490.

    Google Scholar 

  • Kornhuber J., Mack-Burhardt P., and Riederer P. (1989b) Regional distribution of [3H]MK-801 binding sites in the human brain.Brain Res. 489: 397–399.

    Google Scholar 

  • Lavoie J., Giguere J.F., Pomier Layrargues G., and Butterworth R.F. (1987) Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy.J. Neurochem. 49: 692–697.

    Google Scholar 

  • Maddison J.E., Watson W.E.J., Dodd P.R., and Johnston G.A.R. (1991) Alterations in cortical [3H]kainate and a-[3H]amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding in a spontaneous canine model of chronic hepatic encephalopathy.J. Neurochem. 56:1881–1888.

    Google Scholar 

  • Moroni F., Lombardi G., Moneti G., and Cortesini C. (1983) The release and neosynthesis of glutamic acid are increased in experimental models of hepatic encephalopathy.J. Neurochem. 40: 850–854.

    Google Scholar 

  • Mukherjee G., Caron M.G., and Lefkowitz R.J. (1985) Catecholamine induced subsensitivity of adenylate cyclase associated with loss of 1-adrenergic receptor binding sites.Proc. Natl. Acad. Sci. USA. 27:1945–1949.

    Google Scholar 

  • Munson P.J. and Rodbard D. (1980) LIGAND: a versatile computerized approach for characterization of ligand-binding systems.Anal. Biochem. 107: 220.

    Google Scholar 

  • Norenberg M.D. and Gregorius J.B. (1985) Central nervous system manifestations of systemic disease, in Textbook of neuropathology (Davis R.L. and Robertson D.M., eds), pp 403–467, Williams and Wilkins.

  • Peterson C., Giguere J.F., Cotman C.W., and Butterworth R.F. (1990) Selective loss of N-methyl-D-aspartate-sensitive L-[3H]glutamate binding sites in rat brain following portacaval anastomosis.J. Neurochem. 55: 386–390.

    Google Scholar 

  • Phillips G.B., Schwartz R., Gabuzda G.J., and Davidson C.S. (1952) The syndrome of the impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances.N. Engl. J. Med. 247: 239–246.

    Google Scholar 

  • Quarum M.L., Parker J.D., Keana J.F.W. and Weber E. (1990) (+)-[3H]MK-801 binding sites in postmortem human brain.J. Neurochem. 54: 1163–1168.

    Google Scholar 

  • Ramoa A.S., Alkondon M., Irons J., Lunt G.G., Deshpande S.S., Wonnacott S., Aronstam R.S. and Albuquerque E.X. (1990) The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels.J. Pharmacol. Exp. Ther. 254: 71–82.

    Google Scholar 

  • Rao V.L.R., Agrawal A.K. and Murthy Ch.R.K. (1991) Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes.Neurosci. Lett. 130: 251–254.

    Google Scholar 

  • Rao V.L.R., Murthy Ch.R.K. and Butterworth R.F. (1992) Glutamatergic synaptic dysfunction in hyperammonemic syndromes.Metabol. Brain Dis. 7: 1–20.

    Google Scholar 

  • Rothman S.M. and Olney J.W. (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage.Am. Neurol. 19: 105–111.

    Google Scholar 

  • Rothman S.M. and Olney J.W. (1987) Excitotoxicity and the NMDA receptor.TINS 10: 299–302.

    Google Scholar 

  • Van Sande M., Mardens Y., Adriaenssens K., Lowenthal A. (1970) The free amino acids in human cerebrospinal fluid.J. Neurochem. 17: 125–135.

    Google Scholar 

  • Schenker S. (1989) Hepatic encephalopathy: the present and the future, in Hepatic encephalopathy. Pathophysiology and treatment. (Butterworth R.F. and Pomier Layrargues G., eds), pp 3–24, Humana Press, Clifton.

    Google Scholar 

  • Stahl J. (1963) Studies of the blood ammonia in liver disease. Its diagnostic, prognostic and therapeutic significance.Ann. Intern. Med. 58: 1–24.

    Google Scholar 

  • Steele J.E., Robinson T.N., Cross A.J., Bowen D.M. and Green A.R. (1991) A comparison of [3H]MK-801 and N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine binding to the N-methyl-D-aspartate receptor complex in human brain.J. Neurochem. 56: 1248–1254.

    Google Scholar 

  • Swain M.S., Butterworth R., and Blei A.T. (1991) Brain ammonia and brain edema in experimental acute liver failure, in Progress in hepatic encephalopathy and metabolic nitrogen exchange (Bengtsson F., Jeppsson B., Almdal T., Vilstrup H., eds), pp 243–250, CRC Press, Boca Raton.

    Google Scholar 

  • Swain M.S., Bergeron M., Audet R., Blei A.T. and Butterworth R.F. (1992) Monitoring of neurotransmitter amino acids by means of an indwelling cistema magna catheter. A comparison of two rodent models of fulminant hepatic failure.Hepatology 16: 1028–1035.

    Google Scholar 

  • Van der Rijt C.C.D., 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.Metabol. Brain. Dis. 5: 131–141.

    Google Scholar 

  • Vergara F., Plum P., and Duffy T.E. (1974) a-Ketoglutaramate: increased concentrations in the cerebrospinal fluid of patients with hepatic coma.Science 183: 81–83.

    Google Scholar 

  • Watanabe A., Takei N., and Higashi T. (1984) Glutamic acid and glutamine levels in serum and cerebrospinal fluid in hepatic encephalopathy.Biochem. Med. 32: 225–231.

    Google Scholar 

  • Watanabe A., Shiota T., Takei N., and Nagashima H. (1985) Excitatory and inhibitory amino acid neurotransmitters and ammonia metabolism in hepatic failure rats.Res. Exp. Med. 185: 399–404.

    Google Scholar 

  • Watanabe A., Fujiwara M., Shiota T., and Tsuji T. (1988) Amino acid neurotransmitters and their receptors in the brain synaptosomes of acute hepatic failure rats.Biochem. Med. Metabol. Biol. 40: 247–252.

    Google Scholar 

  • Wong E.H.F., Knight A.R. and Woodruff G.N. (1988) [3H]MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat membranes.J. Neurochem. 50: 274–281.

    Google Scholar 

  • Zimmermann C., Ferenci P., Pifl C., Yurdaydin C., Ebner J., Lassmann H., Roth E., and Hörtnagl H. (1989) Hepatic encephalopathy in thioacetamide-induced acute liver failure in rats: characterization of an improved model and study of amino acid-ergic neurotransmission.Hepatology 9: 594–601.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Knegt, R.J., Kornhuber, J., Schalm, S.W. et al. Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Metab Brain Dis 8, 81–94 (1993). https://doi.org/10.1007/BF00996891

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00996891

Key words

Navigation