title: Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes.
abstract: Astroglial swelling occurs in acute hyperammonemic states, including acute hepatic encephalopathy. In these conditions, the peripheral-type benzodiazepine receptor (PBR), a receptor associated with neurosteroidogenesis, is up-regulated. This study examined the potential involvement of PBRs and neurosteroids in ammonia-induced astrocyte swelling in culture. At low micromolar concentrations, the PBR antagonist PK 11195, atrial natriuretic peptide, and protoporhyrin IX, which are known to interact with the PBR, attenuated (16-100%) the effects of ammonia, whereas the PBR agonists Ro5-4864, diazepam binding inhibitor (DBI51-70), and octadecaneuropeptide exacerbated (10-15%) the effects of ammonia. At micromolar concentrations, diazepam, which interacts with both the PBR and the central-type benzodiazepine receptor (CBR), increased swelling by 11%, whereas flumazenil, a CBR antagonist, had no effect. However, at 100 nM diazepam and flumazenil abrogated ammonia-induced swelling. The neurosteroids dehydroepiandrosterone sulfate, tetrahydroprogesterone, pregnenolone sulfate, and tetrahydrodeoxycorticosterone (THDOC), products of PBR stimulation, at micromolar concentrations significantly enhanced (70%) ammonia-induced swelling. However, at nanomolar concentrations, these neurosteroids, with exception of THDOC, blocked ammonia-induced swelling. We conclude that neurosteroids and agents that interact with the PBR influence ammonia-induced swelling. These agents may represent novel therapies for acute hyperammonemic syndromes and other conditions associated with brain edema and astrocyte swelling.
authors.affiliation: Veterans Administration Medical Center, Department of Pathology, University of Miami School of Medicine, Florida 33101, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Bender
authors.forename: M D
authors.initials: MD
authors.lastname: Norenberg
mesh_terms: D000641:Ammonia / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000648:ultrastructure; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D001929:Brain Edema / Q000139:chemically induced / Q000517:prevention & control; D048429:Cell Size / Q000187:drug effects; D002998:Clonazepam / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D026261:Diazepam Binding Inhibitor; D005442:Flumazenil / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D009479:Neuropeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000502:physiology*; D013256:Steroids / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001570:Benzodiazepinones; D026261:Diazepam Binding Inhibitor; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D011524:Protoporphyrins; D011963:Receptors, GABA-A; D013256:Steroids; C067529:diazepam binding inhibitor (33-50); C117601:diazepam-binding inhibitor (51-70); C018370:pregnenolone sulfate; D001569:Benzodiazepines; C062525:atrial natriuretic factor prohormone (103-126); C028513:4'-chlorodiazepam; D003900:Desoxycorticosterone; D005442:Flumazenil; C009413:tetrahydrodeoxycorticosterone; D019314:Dehydroepiandrosterone Sulfate; D002998:Clonazepam; D011284:Pregnenolone; D000641:Ammonia; D009320:Atrial Natriuretic Factor; D011280:Pregnanolone; C028025:protoporphyrin IX; D003975:Diazepam; C037850:PK 11195