Abstract
Rationale
Νeurosteroids, like dehydroepiandrosterone (DHEA), play an important role in neurodegeneration and neural protection, but they are metabolized in androgens, estrogens, or other active metabolites. A newly developed synthetic DHEA analog, BNN27 ((20R)-3β,21-dihydroxy-17R,20-epoxy-5-pregnene), exerts neurotrophic and neuroprotective actions without estrogenic or androgenic effects.
Objectives
This study aimed to investigate potential anxiolytic or antidepressant properties of BNN27.
Methods
Male and female adult Wistar rats were treated with BNN27 (10, 30, or 90 mg/kg, i.p.) and subjected to behavioral tests measuring locomotion, exploration, and “depressive-like” behavior (open field, light/dark box, hole-board, and forced swim tests). The hippocampus and prefrontal cortex were collected for glutamate and GABA measurements, and trunk blood was collected for gonadal hormone analysis.
Results
Acute high-dose BNN27 reduced locomotion and exploratory behavior in both sexes. Intermediate acute doses (30 mg/kg) of BNN27 reduced exploration and testosterone levels only in males, and enhanced progesterone levels in both sexes. Notably, with the present design, BNN27 had neither anxiolytic nor antidepressant effects and did not affect estrogen levels. Interestingly, acute administration of a low BNN27 dose (10 mg/kg) increased glutamate turnover, GABA, and glutamine levels in the hippocampus. The same dose also enhanced glutamate levels in the prefrontal cortex of males only. Sex differences were apparent in the basal levels of behavioral, hormonal, and neurochemical parameters, as expected.
Conclusions
BNN27 affects locomotion, progesterone, and testosterone levels, as well as the glutamatergic and GABAergic systems of the hippocampus and prefrontal cortex in a sex-dependent way.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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The authors wish to acknowledge the excellent technical support of Mrs. Despina Papasava.
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NK was involved in all stages of the experimental procedures, data collection, analysis, and interpretation. FD and KA provided insights regarding the behavioral experiments. C. Dioli performed behavioral experiments. RP performed neurochemical measurements. AG, IC, and TC provided the BNN27, as well as gave valuable advice and critically reviewed the manuscript. MGS assisted in the data and manuscript preparation. C. Dalla supervised the project and manuscript preparation.
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All rats were handled in accordance with the guidelines for the care and handling of laboratory animals in EU Directive 2010/63 and the experiments were approved by the local committee (Prefecture of Athens, Greece, protocol number 3288/15 May 2012).
Conflict of interest
NK and CD have received honoraria and financial support from Janssen-Cilag, Elpen S.A. and Medochemie S.A. MGS has received financial support from Mallinckrodt. None of those is relevant to this study. AG is the co-founder of the spin-off Bionature EA LTD, proprietary of compound BNN27 (patented with the WO 2008/1555 34 A2 number at the World Intellectual Property Organization).
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Kokras, N., Dioli, C., Paravatou, R. et al. Psychoactive properties of BNN27, a novel neurosteroid derivate, in male and female rats. Psychopharmacology 237, 2435–2449 (2020). https://doi.org/10.1007/s00213-020-05545-5
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DOI: https://doi.org/10.1007/s00213-020-05545-5