title: Attenuation of ammonia toxicity in mice by PK 11195 and pregnenolone sulfate.
abstract: Ammonia and benzodiazepines are thought to be involved in the pathogenesis of hepatic encephalopathy. The present study was undertaken to evaluate the effect of various benzodiazepine-receptor ligands and neurosteroids on ammonia toxicity in mice. Administration of ammonium acetate (8-15 mmole/kg; i.p.) to Swiss Webster mice resulted in a dose-dependent increase in mortality. Pretreatment with the central benzodiazepine receptor agonist clonazepam or the antagonist Ro15-1788 (7 mg/kg each; i.p.) had no significant effect on the lethal response to 10 mmole/kg ammonium acetate. However, pretreatment with the putative antagonist of the peripheral-type benzodiazepine receptor, PK 11195 (10 mg/kg; i.p.), reduced mortality from 50 to 10%. Ro5-4864 (10 mg/kg; i.p.), an agonist of the peripheral-type benzodiazepine receptors, had no effect on ammonia toxicity. The neurosteroid, pregnenolone sulfate (20 mg/kg; i.p.) reduced mortality from 50 to 25%. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (2 mg/kg; i.p.), had no effect on the lethal response to ammonium acetate. The results from the present study suggest a role for peripheral-type benzodiazepine receptors and specific neurosteroids in the alleviation of ammonia toxicity in mice.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, FL 33101-6129.
authors.forename: Y
authors.initials: Y
authors.lastname: Itzhak
authors.forename: M D
authors.initials: MD
authors.lastname: Norenberg
mesh_terms: D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D002998:Clonazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011284:Pregnenolone / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; C018370:pregnenolone sulfate; D002998:Clonazepam; D016291:Dizocilpine Maleate; D011284:Pregnenolone; D000641:Ammonia; C037850:PK 11195