2002 Curt P. Richter awardNeuroactive steroids: mechanisms of action and neuropsychopharmacological properties
Introduction
Steroid hormone action involves binding of the steroids to their respective intracellular receptors (Evans, 1988, Truss and Beato, 1993, Rupprecht and Holsboer, 1999). These receptors subsequently change their conformation by dissociation from chaperone molecules, e.g. the heat shock proteins, and translocate to the nucleus where they bind as homo- or heterodimers to the respective response elements that are located in the regulatory regions of target promoters. Thus, steroid hormone receptors act as transcription factors in the regulation of gene expression (Evans, 1988, Truss and Beato, 1993, Rupprecht, 1997, Rupprecht and Holsboer, 1999). Meanwhile, there is increasing evidence that certain steroids may alter neuronal excitability via the cell surface through interaction with certain neurotransmitter receptors (Majewska et al., 1986, Paul and Purdy, 1992, Lambert et al., 1995, Rupprecht, 1997, Rupprecht and Holsboer, 1999). The term ‘neuroactive steroids’ has been coined for steroids with these particular properties (Paul and Purdy, 1992). While the action of steroids at the genome requires a time period from minutes to hours that is limited by the rate of protein biosynthesis (McEwen, 1991), the modulatory effects of neuroactive steroids are fast occurring events requiring only milliseconds to seconds (McEwen, 1991). Thus, genomic and non-genomic steroid effects within the central nervous system provide the molecular basis for a broad spectrum of steroid action on neuronal function and plasticity.
Initially, it has been believed that steroid hormones act exclusively through the classical genomic pathway whereas certain neuroactive steroids that do not bind to either known steroid hormone receptor, e.g. 3α-reduced metabolites of progesterone and deoxycorticosterone such as 3α, 5α-tetrahydroprogesterone (3α, 5α-THP; 3α-hydroxy-5α-pregnan-20-one; allopregnanolone) and 3α, 5α-tetrahydrodeoxycorticosterone (3α, 5α-THDOC; 3α, 21-dihydroxy-5α-pregnan-20-one; allotetrahydrodeoxycorticosterone), pregnenolone sulfate (PS) or dehydroepiandrosterone sulfate (DHEA-S) are allosteric modulators of specific neurotransmitter receptors such as γ-aminobutyric acid type A (GABAA) receptors (Evans, 1988, Paul and Purdy, 1992). This concept, however, has been challenged by the identification of binding sites for classical steroid hormones, e.g. progesterone (Ramirez and Zheng, 1996), estradiol (Pappas et al., 1995, Ramirez and Zheng, 1996), testosterone (Ramirez and Zheng, 1996), glucocorticoids (Orchinik et al., 1991) or aldosterone (Wehling, 1997), at membranes of cells or tissues and of a large number of signal transduction pathways involved in steroid hormone action (Wehling, 1997). Moreover, the modulation of ligand-gated ion channels or G-protein coupled receptors by steroids may alter the activity of intracellular kinases, which consequently affects the expression patterns of downstream genes, e.g. via the cyclic AMP-protein kinase A-cyclic AMP reponsive element binding protein (CREB) pathway (Wehling, 1997, Zakon, 1998). The identification of new members of the steroid receptor family, e.g. the pregnane X receptor (PXR) that may be activated by naturally occurring steroids such as pregnenolone and progesterone (Kliewer et al., 1998) but also phytopharmaceuticals such as St John’s wort (Moore et al., 2000) further adds to the high diversity of steroid action in the brain and it is to be expected that future research will reveal even more complexity. On the other hand, it is important to emphasize that a variety of steroid hormones have been identified that interact with different neurotransmitter receptors and thus also need to be defined as neuroactive steroids. Thus, steroids are promiscuous molecules with pleiotropic effects involving both genomic and non-genomic mechanisms of action.
Section snippets
Biosynthesis of neuroactive steroids
Due to their lipophilic nature steroids that are produced in various endocrine organs can easily cross the blood–brain barrier. However, a variety of neuroactive steroids may be synthesized in the brain itself without the aid of peripheral sources (Akwa et al., 1992, Baulieu, 1991, Baulieu, 1998). These steroids that are formed within the brain from cholesterol have been defined also as ‘neurosteroids’(Baulieu, 1998). As excellent reviews are available elsewhere on the biosynthesis and
Steroid modulation of γ-aminobutyric acid type A (GABAA) receptors
The 3α-reduced metabolites of progesterone and deoxycorticosterone 3α, 5α-tetrahydroprogesterone (3α, 5α-THP; 3α-hydroxy-5α-pregnan-20-one; allopregnanolone) and 3α, 5α-tetrahydrodeoxycorticosterone (3α, 5α-THDOC; 3α, 21-dihydroxy-5α-pregnan-20-one; allotetrahydrodeoxycorticosterone) were the first steroids that have been shown to modulate neuronal excitability via their interaction with γ-aminobutyric acid type A (GABAA) receptors (Majewska et al., 1986). GABAA receptors consist of various
Effects of neuroactive steroids on gene expression
For a long time it was assumed that neuroactive steroids modulating GABAA receptors do not regulate gene expression via intracellular steroid receptors because they do not bind to either known steroid hormone receptor (Paul and Purdy, 1992). Using a cotransfection system with recombinant progesterone receptors and the mouse mammary tumor virus (MTV) promoter upstream of the luciferase gene as a reporter gene, we could show that the neuroactive steroids 3α, 5α-THP and 3α, 5α-THDOC effectively
Sleep
In view of the GABA enhancing potential of 3α-reduced neuroactive steroids such steroids are likely to possess sleep modulating properties. Indeed, already early investigations suggested a sleep promoting and hypnotic effect of the 3α-reduced neuroactive steroid 3α, 5α-THDOC (Mendelson et al., 1987). First studies with synthetic analogues of 3α-reduced neuroactive steroids showed that such steroids may shorten sleep latency and thus might be suitable for treatment of sleep disturbances (Edgar
Future perspectives and outlook
Neuroactive steroids may modulate neuronal function through their concurrent influence on neuronal excitability and gene expression (Fig. 13). This intracellular cross-talk between genomic and non-genomic steroid effects provides the molecular basis for steroid action in the brain and the future development of such compounds in neuropsychopharmacology, both with regard to putative clinical effects and side effects. One important issue is specificity. As yet, no naturally occurring steroid with
Acknowledgements
The studies on neuroactive steroids at the Max-Planck-Institute of Psychiatry and the Department of Psychiatry, Ludwig Maximilian University, Munich are supported by the Gerhard Heβ Programm of the Deutsche Forschungsgemeinschaft and the German Federal Research Ministry within the promotional emphasis ‘Competence Nets in Medicine’.
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