Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure.
Three separate, but allosterically interacting, sites on the gamma-aminobutyric acid (GABA) supramolecular complex in the brain were pharmacologically blocked in rabbits with hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure to determine whether decreased GABAergic neurotransmission can ameliorate the syndrome of hepatic encephalopathy. Bicuculline (a GABAA receptor blocker), Ro 15-1788 (a benzodiazepine receptor antagonist), or isopropylbicyclophosphate (a chloride channel blocker) consistently induced a transient but unequivocal decrease in the clinical severity of the encephalopathy and also corrected the abnormal pattern of the visual evoked response associated with hepatic encephalopathy. Rabbits with hepatic encephalopathy exhibited increased resistance to the convulsive effects of bicuculline. In encephalopathies induced in rabbits by gamma-vinyl-GABA (an inhibitor of GABA catabolism) or diazepam (a benzodiazepine receptor agonist), abnormalities of the visual evoked response similar to those found in hepatic encephalopathy occurred and were corrected by bicuculline and Ro 15-1788, respectively. These findings suggest that in hepatic encephalopathy due to fulminant hepatic failure (a) there is increased GABAergic tone, (b) an amelioration of encephalopathy can be induced by blockade of GABA or benzodiazepine receptors, (c) benzodiazepine receptor antagonists may be of clinical value in the management of hepatic encephalopathy, and (d) an endogenous substance with GABA potentiating properties may be present in hepatic encephalopathy.
Bassett
M L
ML
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
Mullen
K D
KD
Skolnick
P
P
Jones
E A
EA
D000818:Animals; D001640:Bicuculline / Q000627:therapeutic use*; D005074:Evoked Potentials, Visual / Q000187:drug effects*; D005442:Flumazenil / Q000627:therapeutic use*; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D011817:Rabbits; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D005442:Flumazenil; C008207:4-isopropylbicyclophosphate; D001640:Bicuculline