TY - JOUR
T1 - Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes
AU - Bender, Alex S.
AU - Norenberg, Michael D.
PY - 1998/12/1
Y1 - 1998/12/1
N2 - 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.
AB - 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.
KW - Ammonia
KW - Astrocyte swelling
KW - Atrial natriuretic peptide
KW - Benzodiazepines
KW - Hepatic encephalopathy
KW - Neurosteroids
KW - Peripheral- type benzodiazepine receptor
KW - Protoporphyrin IX
UR - http://www.scopus.com/inward/record.url?scp=0032401018&partnerID=8YFLogxK
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U2 - 10.1002/(SICI)1097-4547(19981201)54:5<673::AID-JNR12>3.0.CO;2-P
DO - 10.1002/(SICI)1097-4547(19981201)54:5<673::AID-JNR12>3.0.CO;2-P
M3 - Article
C2 - 9843158
AN - SCOPUS:0032401018
VL - 54
SP - 673
EP - 680
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 5
ER -