Detection and Characterization of Endogenous Benzodiazepine Activity in Both Animal Models and Humans with Hepatic Encephalopathy
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.
KeywordsAdenosine Diazepam Xanthine Nicotinamide Uremia
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- 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
- 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
- 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
- 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