EFFECT OF BENZODIAZEPINES AND NEUROSTEROIDS ON AMMONIA-INDUCED SWELLING IN CULTURED ASTROCYTES

Astroglial swelling occurs in acute hyperammonemic states, including a cute hepatic encephalopathy, In these conditions, the peripheral-type benzodiazepine receptor (PBR), a receptor associated with neurosteroid ogenesis, is up-regulated, This study examined the potential involveme nt of PBRs and neurosteroids in ammonia-induced astrocyte swelling in culture, At low micromolar concentrations, the PER antagonist PK 11195 , atrial natriuretic peptide, and protoporhyrin IX, which are known to interact with the PER, attenuated (16-100 %) the effects of ammonia, whereas the PER agonists Ro5-4864, diazepam binding inhibitor (DBI51-7 0), and octadecaneuropeptide exacerbated (10-15%) the effects of ammon ia, At micromolar concentrations, diazepam, which interacts with both the PER 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 s welling, The neurosteroids dehydroepiandrosterone sulfate, tetrahydrop rogesterone, pregnenolone sulfate, and tetrahydrodeoxycorticosterone ( THDOC), products of PER stimulation, at micromolar concentrations sign ificantly enhanced (70%) ammonia-induced swelling, However, at nanomol ar concentrations, these neurosteroids, with exception of THDOC, block ed ammonia-induced swelling, We conclude that neurosteroids and agents that interact with the PER influence ammonia-induced swelling. These agents may represent novel therapies for acute hyperammonemic syndrome s and other conditions associated with brain edema and astrocyte swell ing, Published 1998 Wiley-Liss, Inc.(()dagger