The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy

Michael D. Norenberg, Yossef Itzhak, Alex S. Bender

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Ammonia and astrocytes are inextricably involved in the mechanism of HE. We propose that ammonia, by upregulating the astrocytic peripheral benzodiazepine receptor, results in the production of neurosteroids that exert a positive modulatory effect on the GABA(A) receptor which contributes to the neuroinhibition and neurologic dysfunction associated with hepatic encephalopathy. In support of this hypothesis, we, and others, have shown: 1) that the PBR is upregulated in animal models of hyperammonemia/HE as well as in ammonia-treated astrocyte cultures; 2) that PK 11195, a specific blocker of the PBR, ameliorates ammonia toxicity in vivo; 3) that the synthesis of pregnenolone, the parent compound for all neurosteroids, is increased in ammonia-treated astrocyte cultures and in in vivo models of HE; 4) that levels of THP and THDOC, pregnenolone-derived neurosteroids with positive modulatory effects on the GABA(A) receptor, are elevated in animal models of HE; and 5) neurosteroids exert behavioral and neuropathologic changes similar to HE. This hypothesis integrates the two currently dominant pathogenetic vies of HE, namely, ammonia neurotoxicity and excessive GABAergic tone. The PBR/neurosteroid hypothesis also incorporates the pathogenetic role of astrocytes, the cells in brain principally affected in HE. The presence of the PBR on astrocytes as well as the identification of astrocytes as major sources of neurosteroids serves again to highlight their critical role in the pathogenesis of HE, a disorder which we have reviewed for some time as a primary gliopathy. The potential role of PBR upregulation resulting in increased neurosteroid production offers the potential for exciting novel therapeutic approaches to HE through modulation of neurosteroid effects.

Original languageEnglish (US)
Pages (from-to)95-111
Number of pages17
JournalAdvances in experimental medicine and biology
Volume420
DOIs
StatePublished - 1997

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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