The antidepressant-like effect of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane involves a regulation of β-type estrogen receptors
Abstract
Rationale Trilostane is a competitive inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD), which notably converts pregnenolone into progesterone or dehydroepiandrosterone into androstenedione. Trilostane shows antidepressant-like properties in the forced swimming test (FST). The compound, however, induced only moderate effects on neuroactive steroid levels that could be related to its behavioral efficacy.Methods We compared the behavioral effect of trilostane with the other 3β-HSD inhibitor, cyanoketone, and analyzed the putative involvement of the β-type estrogen receptor (ERβ) in its antidepressant effect.Results Trilostane reduced immobility in the FST significantly at 12.5 and 25 mg/kg subcutaneously (s.c.), whereas cyanoketone (0-100 mg/kg s.c.) was ineffective. The negative ER modulator fulvestrant (ICI 182780) dose-dependently blocked the effect of trilostane (25 mg/kg). Trilostane increased circulating estradiol levels in the 12.5-50 mg/kg dose-range, and this effect was unaffected by stress and not shared by cyanoketone (25 mg/kg). The trilostane (25 mg/kg) treatment increased the ERβ mRNA expression in adrenals (+100%) and centrally, in the hippocampus (+330%). Stress and cyanoketone failed to affect ERβ mRNA levels in periphery or in the brain.Conclusions These data demonstrate that the antidepressant-like potential of trilostane is not due to its 3β-HSD inhibiting activity, since it is not shared by cyanoketone, but rather to its estrogenic activity. The compound, which releases estradiol and up-regulates ERβ receptors, could be used as a therapeutic tool to allow an estrogenic facilitation of antidepressant efficacy.
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Prior work links ESR2 to antidepressant effects via up-regulation by 3β-hydroxysteroid dehydrogenase.
“Estrogen Receptor 2 (ESR2) has previously been implicated in antidepressant action through up-regulation by 3β-hydroxysteroid dehydrogenase 47.”
From Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions (2019) · cites this paper as [47]
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- Authors
- Espallergues, J., Temsamani, J., Laruelle, C., Urani, A., & Maurice, T.
- Affiliations
- Inserm (FR)
- Sanofi (France) (FR)
- Corresponding author
- Maurice, Tangui
- Venue
- Psychopharmacology
- Published
- 2010-10-28
- Volume
- 214
- Issue
- 2
- Pages
- 455-463
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- OpenAlex
- W2041087822
- Cited by
- 8
- References
- 38
- Citations by year
- 2019: 1 · 2018: 2 · 2016: 1 · 2015: 1 · 2013: 1
- FWCI
- 0.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- trilostane, antidepressant-like effects, cyanoketone, estradiol, forced swim test, fulvestrant, hippocampus, adrenal gland, neurosteroids, estrogenic activity, depression
- MeSH terms
- Fulvestrant, Adrenal Glands, Analysis of Variance, Animals, Antidepressive Agents, Behavior, Animal, Cyanoketone, Dose-Response Relationship, Drug, Enzyme Inhibitors, Estradiol, Estrogen Antagonists, Hippocampus, Male, Motor Activity, RNA, Messenger, Dihydrotestosterone, Swimming, Time Factors, 3-Hydroxysteroid Dehydrogenases, Up-Regulation, Estrogen Receptor beta, Mice
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