Advertisement

Detection and Characterization of Endogenous Benzodiazepine Activity in Both Animal Models and Humans with Hepatic Encephalopathy

  • K. D. Mullen
  • K. M. Szauter
  • K. Kaminsky
  • P. D. Tolentino
  • A. J. McCullough
Chapter
Part of the Experimental Biology and Medicine book series (EBAM, volume 22)

Abstract

The search for endogenous ligands for central nervous system benzodiazepine(BZ) receptors and the definition of the fundamental mechanism responsible for the mediation of hepatic encephalopathy(HE) have had parallel courses in futility until very recently.1 These apparently disparate fields of interest have converged because of experimental observations made in animal models of HE. The catalyst for this joining of forces was the development of BZ receptor antagonists. These drugs e.g. Ro 15–1788 (Flumazenil) and CGS-8216 largely devoid of effect in controls reverse the sedative effects of synthetic agonist BZ compounds. Administration of these agents to animal models of HE resulted in considerable amelioration in the manifestations of HE2,3 which has been corroborated to some degree in isolated human reports. While the response in HE was not as complete as that seen with administration of the drug to controls treated with agonist BZ drugs it was of sufficient magnitude to suggest a significant neurological event was taking place which required further study.

Keywords

Hepatic Encephalopathy Fulminant Hepatic Failure Radioreceptor Assay Diazepam Binding Inhibitor Beta Carboline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mullen KD, Martin JV, Mendelson WB, Bassett ML, Jones EA. Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy? Lancet i 457–459,1988.CrossRefGoogle Scholar
  2. 2.
    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 benzodiazepine antagonist. Clin Sci 67:167–175,1984.PubMedGoogle Scholar
  3. 3.
    Bassett ML, Mullen KD, Skolnick P, Jones EA. Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastro 93:1069–1077,1987.Google Scholar
  4. 4.
    Hamon M, Soubrie P. Searching for endogenous ligand(s) of central benzodiazepine receptors. Neurochem Int, 5:663–672,1983.PubMedCrossRefGoogle Scholar
  5. 5.
    File S, Pellow S. Do the intrinsic actions of benzodiazepine receptor antagonists imply the existence of an endogenous ligand for benzodiazepine receptors? In: Advances in Biochemical Psychopharmacology: GABAergic Transmission and Anxiety. Raven Press, New York, 98–107,1986.Google Scholar
  6. 6.
    Schafer DF, Jones EA. Hepatic encephalopathy and the gamma-aminobutryric acid neurotransmitter system. Lancet i, 18–20,1982.CrossRefGoogle Scholar
  7. 7.
    Mullen KD, Martin JV, Bassett ML, et al. Hepatic encephalopathy: A syndrome modulated by an endogenous benzodiazepine ligand? Hepatology 6:1221,1986.CrossRefGoogle Scholar
  8. 8.
    Gammal SH, Geller D, Skolnick P, et al. Unequivocal amelioration of hepatic encephalopathy by benzodiazepine antagonists in a rat model of fulminant hepatic failure. J Hepatol 4. Suppl. 1 S17,1987.Google Scholar
  9. 9.
    Wildmann J, Mohler H, Vetler W, Ranalder V, Schmidt K, Maurer R. Diazepam and N-desmethyldiazepam are found in rat brain and adrenal and may be of plant origin. J Neural Transm 70:383–388,1987.PubMedCrossRefGoogle Scholar
  10. 10.
    Phillis JW, O’Regan MH. The role of adenosine in the central actions of the benzodiazepines. Prog Neuro-psychopharmacol Biol Psychiat, 12,389–404,1988.CrossRefGoogle Scholar
  11. 11.
    Basile AS, Gammal SH, Mullen KD, Jones EA, Skolnick P. Differential responsiveness of cerebellar purkinje neurones to GABA and benzodiazepine receptor ligands in an animal model of hepatic encephalopathy. J of Neuroscience 8:2414–2421,1988.Google Scholar

Copyright information

© The Humana Press Inc. 1989

Authors and Affiliations

  • K. D. Mullen
    • 1
  • K. M. Szauter
    • 1
  • K. Kaminsky
    • 1
  • P. D. Tolentino
    • 1
  • A. J. McCullough
    • 1
  1. 1.Cleveland Metropolitan General HospitalCase Western Reserve UniversityClevelandUSA

Personalised recommendations