Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes

Alex S. Bender, Michael D. Norenberg

Research output: Contribution to journalArticle

81 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)673-680
Number of pages8
JournalJournal of Neuroscience Research
Volume54
Issue number5
DOIs
StatePublished - Dec 1 1998

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Keywords

  • Ammonia
  • Astrocyte swelling
  • Atrial natriuretic peptide
  • Benzodiazepines
  • Hepatic encephalopathy
  • Neurosteroids
  • Peripheral- type benzodiazepine receptor
  • Protoporphyrin IX

ASJC Scopus subject areas

  • Neuroscience(all)

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