title: Hepatic encephalopathy in rats with thioacetamide-induced acute liver failure is not mediated by endogenous benzodiazepines.
abstract: BACKGROUND
  To distinguish whether the improvement of hepatic encephalopathy by benzodiazepine receptor antagonists is mediated by their antagonistic or their inverse agonistic properties, the neurobehavioral effects of a variety of benzodiazepine receptor ligands in rats with thioacetamide-induced acute liver failure were tested.
  
  
  METHODS
  The neural inhibitory effect of the benzodiazepine agonist flunitrazepam and its reversibility by the "pure" antagonist Ro 14-7437 were examined in thioacetamide-treated rats and controls. The effects of Ro 14-7437, of the partial inverse agonist Ro 15-4513, and the inverse agonist DMCM in rats with hepatic encephalopathy grade II/III were tested. Encephalopathic rats were pretreated with Ro 14-7437 or vehicle and then injected with Ro 15-4513.
  
  
  RESULTS
  Thioacetamide-treated rats were more sensitive to flunitrazepam than controls. In both groups, its effect was completely antagonized with Ro 14-7437. Encephalopathy was significantly improved by Ro 15-4513, although Ro 14-7437 and vehicle had no effect. DMCM worsened the condition of encephalopathic rats but had no effect in controls. Pretreatment with Ro 14-7437 abolished the beneficial effects of Ro 15-4513.
  
  
  CONCLUSIONS
  In rats with thioacetamide-induced liver failure, endogenous benzodiazepines do not precipitate hepatic encephalopathy. The amelioration of hepatic encephalopathy is mediated by benzodiazepine receptor ligands with both antagonistic and inverse agonistic properties.
authors.affiliation: Department of Gastroenterology and Hepatology, University of Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Püspök
authors.forename: A
authors.initials: A
authors.lastname: Herneth
authors.forename: P
authors.initials: P
authors.lastname: Steindl
authors.forename: P
authors.initials: P
authors.lastname: Ferenci
mesh_terms: D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000209:etiology* / Q000503:physiopathology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000009:adverse effects*
chemical_list: D001386:Azides; D002243:Carbolines; D003292:Convulsants; D013853:Thioacetamide; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005445:Flunitrazepam; C038674:Ro 14-7437; C042957:Ro 15-4513