Sex-specific hypnotic effects of the neuroactive steroid (3β, 5β, 17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid. (February 2023)

• Record Type: Journal Article
• Authors: Manzella, Francesca M.; Cabrera, Omar H.; Wilkey, Davis; Fine-Raquet, Brier; Klawitter, Jelena; Krishnan, Kathiresan; Covey, Douglas F.; Jevtovic-Todorovic, Vesna; Todorovic, Slobodan M.
• Is Part Of: British journal of anaesthesia. Volume 130:Number 2(2023)
• Page Start: 154
• Page End: 164
• Publication Date: 2023-02
• Subjects: calcium channels -- electroencephalogram -- metabolism -- neuroactive steroid -- pharmacokinetics -- sex-specific pharmacology; Anesthesiology -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1016/j.bja.2022.09.025
• Languages: English
• ISSNs: 0007-0912

Abstract

Abstract: Background: The novel synthetic neuroactive steroid (3β, 5β, 17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) blocks T-type calcium channels but does not directly modulate neuronal γ-aminobutyric acid type A (GABAA ) currents like other anaesthetic neurosteroids. As 3β-OH has sex-specific hypnotic effects in adult rats, we studied the mechanism contributing to sex differences in its effects. Methods: We used a combination of behavioural loss of righting reflex, neuroendocrine, pharmacokinetic, in vitro patch-clamp electrophysiology, and in vivo electrophysiological approaches in wild-type mice and in genetic knockouts of the CaV 3.1 T-type calcium channel isoform to study the mechanisms by which 3β-OH and its metabolite produces sex-specific hypnotic effects. Results: Adult male mice were less sensitive to the hypnotic effects of 3β-OH compared with female mice, and these differences appeared during development. Adult males had higher 3β-OH brain concentrations despite being less sensitive to its hypnotic effects. Females metabolised 3β-OH into the active GABAA receptor positive allosteric modulator (3α, 5β, 17β)-3-hydroxyandrostane-17-carbonitrile (3α-OH) to a greater extent than males. The 3α-OH metabolite has T-channel blocking properties with sex-specific hypnotic and pharmacokinetic effects. Sex-dependent suppression of the cortical electroencephalogram is more pronounced with 3α-OH compared with 3β-OH. Conclusions: The sex-specific differences in the hypnotic effect of 3β-OH in mice are attributable to differences in its peripheral metabolism into the more potent hypnotic metabolite 3α-OH.