Steroid receptor-mediated effects of neuroactive steroids: Characterization of structure-activity relationship

Rainer Rupprecht*, Barbara Berning, Charlotte Hauser, Florian Holsboer, Johannes M.H.M. Reul

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Neuroactive steroids rapidly alter neuronal excitability through their action via the cell surface. The 3 α-hydroxy ring A-reduced pregnane steroids enhance γ-aminobutyric acid (GABA)-mediated Cl- currents while pregnenolone sulfate and dehydroepiandrosterone sulfate may exert functional antagonistic properties. Based on our previous findings that the 3 α-hydroxy ring A-reduced pregnane steroids allotetrahydroprogesterone and allotetrahydrodeoxycorticosterone may regulate gene expression via the progesterone receptor after intracellular oxidation, we have characterized the effects of a series of natural and synthetic neuroactive steroids at the genomic level using a cotransfection system with various steroid receptor expression vectors and a reporter gene in a human neuroblastoma cell line. Pregnanolone and pregnenolone were able to activate both the chicken and the human progesterone receptor while the synthetic 3 α-hydroxylated derivative alphaxalone and dehydroepiandrosterone were active via the chicken progesterone receptor but devoid of transcriptional activity via the human progesterone receptor. Moreover, the antiglucocorticoid activity of dehydroepiandrosterone reported at the systemic level could not be reconstituted in the cellular cotransfection system. None of the neuroactive steroids bound directly to steroid receptors. Thus, their genomic activity appears to be mediated via intracellular metabolization. This study provides evidence for differential genomic effects of neuroactive steroids in a structure-specific and species-specific way that may have impact on the development of these steroids for therapeutic application.

Original languageEnglish (US)
Pages (from-to)227-234
Number of pages8
JournalEuropean Journal of Pharmacology
Volume303
Issue number3
DOIs
StatePublished - May 15 1996

Keywords

  • gene expression
  • neuroactive steroid
  • neurosteroid
  • progesterone receptor

ASJC Scopus subject areas

  • Pharmacology

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