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

Manzella, Francesca M.; Cabrera, Omar H.; Wilkey, Davis; Fine-Raquet, Brier; Klawitter, Jelena; Krishnan, Kathiresan; Covey, Douglas F.; Jevtović-Todorović, Vesna; Todorović, Slobodan M.

doi:10.1016/j.bja.2022.09.025

Cited by 3 publications

(3 citation statements)

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“…NS have subsequently been shown to have specific interactions with a variety of proteins including GABA A receptors, glycine receptors, tubulin, voltage-dependent anion channel-1 and -2 (VDAC), liver X receptors (LXR), pregnane X receptors (PXR) and T-type Ca 2+ channels. It has recently been suggested that 3β-OH NS may be anesthetics that act via T-type Ca 2+ channels, rather than GABA A receptors [ 43 , 44 ]. The effect of these agents is slow in onset and is more pronounced in female animals, reminiscent of the earlier work by Selye.…”

Section: The Functional Effect Of Neurosteroids On the Gaba ...mentioning

confidence: 99%

“…The effect of these agents is slow in onset and is more pronounced in female animals, reminiscent of the earlier work by Selye. It has subsequently been shown that the 3β-OH NS anesthetics are metabolized peripherally to 3α-OH NS which can act as GABA-ergic anesthetics [ 44 ]. Genetic knockout of T-type Ca2 + channels does produce some shift in NS anesthetic response, suggesting a possible minor contribution of these channels to NS anesthesia.…”

Section: The Functional Effect Of Neurosteroids On the Gaba ...mentioning

confidence: 99%

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Neurosteroids and their potential as a safer class of general anesthetics

Tateiwa,

Evers

2024

J Anesth

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Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABAA) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed.

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Section: The Functional Effect Of Neurosteroids On the Gaba ...mentioning

confidence: 99%

Section: The Functional Effect Of Neurosteroids On the Gaba ...mentioning

confidence: 99%

Neurosteroids and their potential as a safer class of general anesthetics

Tateiwa,

Evers

2024

J Anesth

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“…The 3α-OH metabolite also has T-channel blocking properties with sex-specific hypnotic and pharmacokinetic effects similar to those of 3β-OH. Interestingly, the peripheral conversion of 3β-OH to 3α-OH is more prominent in adult female than in adult male rats and likely contributes to the stronger hypnotic properties of 3β-OH in females [36]. Although it is not known if similar peripheral metabolic pathways of 3β-OH exist in neonatal rodents, the important question was posed whether 3β-OH would be a safe hypnotic in very young animals.…”

Section: Neuroactive Steroids As Promising Anesthetic Agentsmentioning

confidence: 99%

The Role of Neuroactive Steroids in Analgesia and Anesthesia: An Interesting Comeback?

Jevtovic-Todorovic,

Todorovic

2023

Biomolecules

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Published evidence over the past few decades suggests that general anesthetics could be neurotoxins especially when administered at the extremes of age. The reported pathology is not only at the morphological level when examined in very young and aged brains, given that, importantly, newly developing evidence suggests a variety of behavioral impairments. Since anesthesia is unavoidable in certain clinical settings, we should consider the development of new anesthetics. A promising and safe solution could be a new family of anesthetics referred to as neuroactive steroids. In this review, we summarize the currently available evidence regarding their anesthetic and analgesic properties.

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5β-Dihydrosteroids: Formation and Properties

Penning,

Covey

2024

IJMS

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5β-Dihydrosteroids are produced by the reduction of Δ4-3-ketosteroids catalyzed by steroid 5β-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the 5α-dihydrosteroids (e.g., 5α-dihydrotestosterone), the 5β-dihydrosteroids produced by AKR1D1 are not inactive but regulate ligand access to nuclear receptors, can act as ligands for nuclear and membrane-bound receptors, and regulate ion-channel opening. For example, 5β-reduction of cortisol and cortisone yields the corresponding 5β-dihydroglucocorticoids which are inactive on the glucocorticoid receptor (GR) and provides an additional mechanism of pre-receptor regulation of ligands for the GR in liver cells. By contrast, 5β-pregnanes can act as neuroactive steroids at the GABAA and NMDA receptors and at low-voltage-activated calcium channels, act as tocolytic agents, have analgesic activity and act as ligands for PXR, while bile acids act as ligands for FXR and thereby control cholesterol homeostasis. The 5β-androstanes also have potent vasodilatory properties and work through blockade of Ca2+ channels. Thus, a preference for 5β-dihydrosteroids to work at the membrane level exists via a variety of mechanisms. This article reviews the field and identifies gaps in knowledge to be addressed in future research.

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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

Cited by 3 publications

References 28 publications

Neurosteroids and their potential as a safer class of general anesthetics

Neurosteroids and their potential as a safer class of general anesthetics

The Role of Neuroactive Steroids in Analgesia and Anesthesia: An Interesting Comeback?

5β-Dihydrosteroids: Formation and Properties

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