The contribution of endogenous benzodiazepine receptor ligands to the pathogenesis of hepatic encephalopathy
- National Institutes of Health, Betheda, MD (USA)
The involvement of the gamma-aminobutyric acid A(GABAA) receptor complex in the pathogenesis of hepatic encephalopathy (HE) was examined in galactosamine-treated rabbits with HE caused by fulminant hepatic failure. Radioligand binding to the constituent components of the GABAA receptor complex was unchanged in rabbits with HE. However, partially purified extracts from encephalopathic rabbit brain were approximately three times more potent in inhibiting ({sup 3}H)Ro 15-1788 binding to benzodiazepine (BZ) receptors than extracts from control rabbits. The inhibition of radioligand binding to the BZ receptor produced by these extracts was competitive and reversible and was significantly enhanced by GABA. Further purification of these extracts by high-performance liquid chromatography (HPLC) indicated that the inhibitory activity was localized in several peaks, some of which had retention times corresponding to 1,4-benzodiazepine standards. The presence of diazepam in these extracts was confirmed using mass spectroscopy. Both mass spectroscopic and radiometric techniques demonstrated that the concentration of diazepam in brain extracts from encephalopathic rabbits was approximately 4 times greater than control extracts. These findings link the presence of BZ receptor agonists to the development of a neuropathological condition, thereby providing a rational basis for the use of BZ receptor antagonists in the management of HE in man.
- OSTI ID:
- 5682023
- Journal Information:
- Synapse (New York); (USA), Vol. 7:2; ISSN 0887-4476
- Country of Publication:
- United States
- Language:
- English
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DIGESTIVE SYSTEM DISEASES
PATHOGENESIS
LIGANDS
BIOLOGICAL FUNCTIONS
SYMPATHOMIMETICS
RECEPTORS
AMINOBUTYRIC ACID
BIOCHEMICAL REACTION KINETICS
BRAIN
LIQUID COLUMN CHROMATOGRAPHY
MASS SPECTROSCOPY
NERVES
RABBITS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMINO ACIDS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BODY
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM
CHROMATOGRAPHY
DISEASES
DRUGS
FUNCTIONS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
NEUROREGULATORS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
REACTION KINETICS
SEPARATION PROCESSES
SPECTROSCOPY
VERTEBRATES
550901* - Pathology- Tracer Techniques