Future Perspectives

Based on their unique molecular properties, neurosteroids have a promising psychop-harmacological profile. Future systemical studies will have to consider both the membrane and the genomic effects of neurosteroids. New synthetic derivatives should allow to separate the transcriptional effects of these steroids from their modulatory effects on neuronal excitability, both with regard to their eventual clinical effects and their potential side effects. For clinical purposes, substances with a sufficient bioavailability after oral administration would be desirable. In addition, pharmacokinetic properties have to be taken into consideration, e.g., linear or U-shaped dose-response curves in animal and clinical studies.

In conclusion, neurosteroids may either modulate neuronal excitability via their interactions with respective neurotransmitter receptors, or may regulate gene expression via PRs (Fig. 9). This intracellular cross-talk between nongenomic and genomic effects of neurosteroids provides the molecular basis for the future development of neurosteroids in neuropsychopharmacology both with regard to clinical effects and to potential side effects.

Fig. 9. Nongenomic and genomic properties of neurosteroids. Progesterone receptor (PR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), heat-shock protein 90 (HSP 90). THP,3a,5a-THPROG; THDOC, 3a,5a-THDOC.

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