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3a,5a-TH PROG

Fig. 3. Biosynthesis and metabolism of neurosteroids.

% Activity % Activity

% Activity % Activity

Fig. 4. Maximal biological activity (mean ± SD) of progestins and 5a-reduced neurosteroids at the level of gene expression measured by the induction of the MMTV promoter for the chicken (cPR ) (left panel) and the human progesterone receptor (hPR ) (right panel). (Adapted with permission from ref. 29.) (5a(|3)-DHP, 5a(P)-DHPROG; THP, 3a,B5a-THPROG; THDOC, 3a,5a-THDOC).

Fig. 4. Maximal biological activity (mean ± SD) of progestins and 5a-reduced neurosteroids at the level of gene expression measured by the induction of the MMTV promoter for the chicken (cPR ) (left panel) and the human progesterone receptor (hPR ) (right panel). (Adapted with permission from ref. 29.) (5a(|3)-DHP, 5a(P)-DHPROG; THP, 3a,B5a-THPROG; THDOC, 3a,5a-THDOC).

observation that alphaxalone, in contrast to its natural analogue 3a,5a-THPROG, was devoid of any transcriptional activity via the hPR. Thus, modifications within the C-ring of these molecules appear to offer a possibility of creating synthetic neurosteroids that maintain their modulatory activity via the GABAA receptor, but are devoid of genomic activity via the hPR (29).

NEUROPSYCHOPHARMACOLOGICAL PROPERTIES OF NEUROSTEROIDS: BEHAVIORAL AND CLINICAL STUDIES

The molecular properties of neurosteroids suggest a potential psychopharmacological profile of the different types of neurosteroids. Indeed, preclinical animal studies have suggested potential benefits of various neurosteroids for certain neuropsychiatry disorders. Though clinical studies are thus far rare, first clinical investigations support the results of animal studies.

Systemic Effects of Pregnenolone

Pregnenolone (PREG) may be converted to an array of steroids; nevertheless, behavioral studies have suggested a potential role for PREG, in particular in memory enhancement. Intracerebroventricular administration of PREG and PREGS leads to an amelioration in various memory tasks in rodents (30). These memory-enhancing effects might be attributable to the N-methyl-D-aspartate (NMDA)-agonistic properties of PREGS (31), since NMDA antagonists have been shown to impair cognitive functions in rodents (32,33). However, valid clinical data concerning the memory enhancing properties of PREG in dementia disorders are lacking to date. PREG formation may be increased also indirectly via the diazepam binding inhibitor (DBI) (34), which may offer additional treatment strategies.

Studies of the effects of PREG on sleep in the rat revealed an increase in electroencephalogram (EEG) activity in the delta frequency range that was contrary to the effects of the benzodiazepine hypnotic midazolam (35). In accordance with this animal study, first clinical investigations evaluating the effects of orally administered PREG on sleep-EEG parameters in human volunteers were in line with partial, inverse agonistic properties of PREG at the GABAa receptor (36). PREG increased the time spent in slow-wave sleep and depressed sigma EEG power during non-REM sleep (36) (Fig. 5). The inverse GABA-agonistic effects of systemically administered PREG as revealed by the sleep-EEG studies may contribute to the understanding of the potential memory enhancing properties of this neurosteroid.

Systemic Effects of Dehydroepiandrosterone (DHEA)

In view of certain similarities in the molecular mechanisms of action between DHEAS and PREGS, memory-enhancing properties should occur also in systemical studies with DHEA. In fact, DHEA has been also shown to enhance memory retention in mice (37). In an animal model of depression, a transgenic mouse model bearing an antisense against the glucocorticosteroid receptor with an impairment of glucocorticoid receptor function, DHEA may reverse cognitive deficits (A. Montkowski et al., unpublished observations). In addition to the effects of DHEA via the cell membrane, potential antigluco-corticosteroid effects of DHEA reported in vivo (38,39) may contribute to its behavioral effects. First clinical studies have shown an increase in REM sleep after oral administra-

1 mg Pregnenolone p.o.

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