Neurosteroids and the Nervous System

King, Steven R.

doi:10.1007/978-1-4614-5559-2

Cited by 11 publications

(5 citation statements)

References 831 publications

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“…Neurosteroids and their synthetic analogs (neuroactive steroids, NAS) have been extensively studied during last three decades as they modify neuronal activity and thus brain function via a fast, non-genomic action (Rebas et al, 2017), by acting as allosteric modulators of various ligandgated ion channels, including GABA A R and GlyR. In brief, NS and NAS are effective modulators of GABA A R-induced chloride current (I GABA ) and their modulatory action is dependent on their structure and subtype (for a review, see: Majewska et al, 1988;Wu et al, 1990;Belelli and Lambert, 2005;Korinek et al, 2011;King, 2013;Zorumski et al, 2013). Those that potentiate GABA activity are termed as "potentiating NS" and these include, e.g., allopregnanolone (3α-hydroxy-5α-pregnan-20-one) or pregnanolone (3α-hydroxy-5β-pregnan-20-one) (Park-Chung et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

Bukanova

Solntseva

Kudová

2020

Front. Mol. Neurosci.

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The ability of androstane and androstene neurosteroids with modifications at C-17, C-5, and C-3 (compounds 1-9) to influence the functional activity of inhibitory glycine and γ-aminobutyric acid (GABA) receptors was estimated. The glycine-and GABAinduced chloride current (I Gly and I GABA) were measured in isolated pyramidal neurons of the rat hippocampus and isolated rat cerebellar Purkinje cells, correspondingly, using the patch-clamp technique. Our results demonstrate that all the nine neurosteroids display similar biological activity, namely, they strongly inhibited I Gly and weakly inhibited I GABA. The threshold concentration of neurosteroids inducing effects on I Gly was 0.1 µM, and for effects on I GABA was 10-50 µM. Moreover, our compounds accelerated desensitization of the I Gly with the IC 50 values varying from 0.12 to 0.49 µM and decreased the peak amplitude with IC 50 values varying from 16 to 22 µM. Interestingly, our study revealed that only compounds 4 (epiandrosterone) and 8 (dehydroepiandrosterone) were able to cause a significant change in I GABA in 10 µM concentration. Moreover, compounds 3 (testosterone), 5 (epitestosterone), 6 (dihydroandrostenedione), and 9 (etiocholanedione) did not modulate I GABA up to the concentration of 50 µM. Thus, we conclude that compounds 3, 5, 6, and 9 may be identified as selective modulators of I Gly. Our results offer new avenues of investigation in the field of drug-like selective modulators of I Gly .

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Section: Introductionmentioning

confidence: 99%

Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

Bukanova

Solntseva

Kudová

2020

Front. Mol. Neurosci.

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“…The enzymes 5α-reductase and 3α-hydroxysteroid-dehydrogenase (3α-HSD) metabolize progesterone to 3α-5α-tetrahydroprogesterone (also known as allopregnanolone) and testosterone to 5α-androstane-3α,17β-diol (also known as 3α-androstanediol) in a parallel manner (Figure 1) (King, 2013;Reddy, 2010). Allopregnanolone is a potent positive allosteric modulator of GABA action at GABA A receptors increasing GABA activity with 10 times the potency of benzodiazepines (King, 2013;Majewska et al, 1986;Morrow et al, 1987). Although less potent than allopregnanolone, 3α-androstanediol is also a positive modulator of GABA A receptor action (Reddy, 2004).…”

Section: Introductionmentioning

confidence: 99%

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

Dichtel

Lawson

Schorr

et al. 2017

Neuropsychopharmacol.

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3α-5α-Tetrahydroprogesterone, a progesterone metabolite also known as allopregnanolone, and 5α-androstane-3α,17β-diol, a testosterone metabolite also known as 3α-androstanediol, are neuroactive steroids and positive GABA A receptor allosteric modulators. Both anorexia nervosa (AN) and obesity are complicated by affective comorbidities and hypothalamic-pituitary-gonadal dysregulation. However, it is not known whether neuroactive steroid levels are abnormal at the extremes of the weight spectrum. We hypothesized that serum allopregnanolone and 3α-androstanediol levels would be decreased in AN compared with healthy controls (HC) and negatively associated with affective symptoms throughout the weight spectrum, independent of body mass index (BMI). Thirty-six women were 1 : 1 age-matched across three groups: AN, HC, and overweight/obese (OW/OB). AN were amenorrheic; HC and OW/OB were studied in the follicular phase. Fasting serum neuroactive steroids were measured by gas chromatography/mass spectrometry. Mean Hamilton depression and anxiety scores were highest in AN (po0.0001). Mean serum allopregnanolone was lower in AN and OW/OB than HC (AN 95.3 ± 56.4 vs OW/OB 73.8 ± 31.3 vs HC 199.5 ± 167.8 pg/ml, p = 0.01), despite comparable mean serum progesterone. Allopregnanolone levels, but not progesterone levels, were negatively associated with depression and anxiety symptom severity, independent of BMI. Serum 3α-androstanediol levels did not differ among groups and were not associated with depression or anxiety scores, despite a significant negative association between free testosterone levels and both anxiety and depression severity. In conclusion, women at both extremes of the weight spectrum have low mean serum allopregnanolone, which is associated with increased depression and anxiety severity, independent of BMI. Neuroactive steroids such as allopregnanolone may be potential therapeutic targets for depression and anxiety in traditionally treatment-resistant groups, including AN.

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“…Pregnanolone is produced in the brain, adrenals, and male and female gonads via a two-step metabolism of P 4 . Initially, P 4 is metabolized into 5α-dihydroP 4 (5α-DHP) by 5α-reductase which is then converted into 3α-5α-tetrahydroP 4 (allopregnanolone [41]). According to Kimball et al [40], less P 4 is converted into allopregnanolone as the cycle progresses from the estrogen-dominated follicular phase to the P 4 -dominated luteal phase of the menstrual cycle.…”

Section: Discussionmentioning

confidence: 99%

Testosterone and Prolactin Perturbations Possibly Associated with Reduced Levels of β-Arrestin1 in Mononuclear Leukocytes of Women with Premenstrual Dysphoric Disorder

Nayyar,

Archibong,

Nayyar

2023

IJMS

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Previously, we reported that a reduction in β-Arrestin1 protein levels in peripheral blood mononuclear leukocytes (PBMC) significantly correlated with the severity of depression symptoms in women with premenstrual dysphoric disorder (PMDD). This study aimed to determine whether the reduced premenstrual β-Arrestin1 protein levels were associated with changes in the regulator for late luteal phase progesterone secretion. The study participants (n = 25) were non-pregnant women between 18 and 42 years of age not taking any antidepressants or receiving therapy and experiencing the luteal phase of menstruation. ELISA determined the β-Arrestin1 protein in PBMC; testosterone and prolactin levels from the plasma were determined by radioimmunoassay. Reduced levels of β-Arrestin1 protein in women with Hamilton Rating Scale for Depression (HAM-D) scores above 19 were observed alongside significantly higher plasma testosterone and prolactin concentrations. Understanding the mechanism underlying the initiation of PMDD will allow for identification of a key perturbed metabolic enzyme that can serve as a target for drug development to ensure the alleviation of PMDD, which has been suggested earlier as a risk factor for developing major depressive disorders.

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Neurosteroids and the Nervous System

Cited by 11 publications

References 831 publications

Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

Testosterone and Prolactin Perturbations Possibly Associated with Reduced Levels of β-Arrestin1 in Mononuclear Leukocytes of Women with Premenstrual Dysphoric Disorder

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