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Recent Advances in Steroid Research and Nervous System Function

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Lipids".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 20373

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Special Issue Editor

Dr. Monique Vallée

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Guest Editor

INSERM U1215, Neurocentre Magendie, Physiopathology and Therapeutic Approaches of Stress-Related Diseases, F33077 Bordeaux, France
Interests: neurosteroid; pregnenolone; endocannabinoid system; physiopathology; cannabis-use disorders, cognitive disorders; translational & clinical research; steroid metabolomics analysis

Special Issue Information

Dear Colleagues,

Steroid research—with the discovery of new steroidogenic sites and innovative mechanisms of steroid action in recent decades—has focused on neurosteroids and neuroactive steroids, encompassing molecular to behavioral domains, with an exponential emphasis on translational and clinical research.

A major discovery involves the de novo production of steroids by the brain, called neurosteroids. One of the major pieces of evidence regarding the neurosteroid concept emerged through the demonstration of the expression and bioactivity of key steroidogenic enzymes in neurons or glial cells of the central and peripheral nervous system of various animal species. In addition, the term neuroactive steroids was coined to represent any steroidal compound, regardless of its source, capable of rapidly modulating nerve cell activity via the membrane–receptor interface independently of the classical targets (i.e., nuclear receptors) of steroids.

Increasing knowledge of steroids, including metabolomic analysis of steroids and their molecular substrates of action, is leading to emerging translational research in animal models of nervous system disorders and providing clinically relevant applications.

We invite investigators to contribute high-quality original research or review articles focused on steroid and nervous system function, including studies on sex steroids, estrogens and androgens, and progesterone, which act on their specific receptor; DHEA, allopregnanolone (and their sulfated derivatives), which target NMDA and GABAA receptors; and, finally, pregnenolone, which is no longer considered an inactive steroidal precursor since the recent discovery of its action as a negative allosteric modulator of the CB1 cannabinoid receptor.

We welcome discussions regarding translational strategies using modulators of steroidogenesis or steroid analogs for the identification of potential treatments for nervous system dysfunction and disorders, such as stress-related diseases, substance use disorders, mood disorders, learning and memory deficits, as well as neuropathic pain, stroke, and neurodegenerative diseases.

Dr. Monique Vallée
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Neurosteroids
Neuroactive steroids
Brain mechanisms
Translational Research
Neuropsychiatry
Neuroprotection
Neuroinflammation
Cognition
Stress
Addiction

Published Papers (7 papers)

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Research

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22 pages, 4391 KiB

Open AccessArticle

Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats

by Giorgia Boero, Minna H. McFarland, Ryan E. Tyler, Todd K. O’Buckley, Samantha L. Chéry, Donita L. Robinson, Joyce Besheer and A. Leslie Morrow

Biomolecules 2023, 13(8), 1205; https://doi.org/10.3390/biom13081205 - 01 Aug 2023

Viewed by 1048

Abstract

The neurosteroid 3α,5α-THP is a potent GABA_A receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous preclinical and clinical studies. We previously demonstrated that 3α,5α-THP down-regulation of HPA axis activity during stress is sex-, brain region- and stressor-dependent. In this study, we observed a deleterious submersion behavior in response to 3α,5α-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3α,5α-THP might affect behavioral coping strategies engaged in by the animal. Given the well-established involvement of the opioid system in HPA axis activation and its interaction with GABAergic neurosteroids, we explored the synergic effects of 3α,5α-THP/opiate system activation in this behavior. Serum β-endorphin (β-EP) was elevated by FSS and enhanced by 3α,5α-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3α,5α-THP + FSS. Pretreatment with the MOP antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2 mg/kg, IP) reversed submersion behavior in males. Moreover, in both males and females, CTAP pretreatment decreased immobility episodes while increasing immobility duration but did not alter swimming duration. This interaction between 3α,5α-THP and the opioid system in the context of FSS might be important in the development of treatment for neuropsychiatric disorders involving HPA axis activation. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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24 pages, 2578 KiB

Open AccessCommunication

Applied Clinical Tandem Mass Spectrometry-Based Quantification Methods for Lipid-Derived Biomarkers, Steroids and Cannabinoids: Fit-for-Purpose Validation Methods

by Isabelle Matias, Ilaria Belluomo, Pierre-Louis Raux and Monique Vallée

Biomolecules 2023, 13(2), 383; https://doi.org/10.3390/biom13020383 - 17 Feb 2023

Cited by 2 | Viewed by 1607

Abstract

The emergence of metabolomics and quantification approaches is revealing new biomarkers applied to drug discovery. In this context, tandem mass spectrometry is the method of choice, requiring a specific validation process for preclinical and clinical applications. Research on the two classes of lipid mediators, steroids and cannabinoids, has revealed a potential interaction in cannabis addiction and metabolism-related disorders. Here we present the development of GC-MS/MS and LC-MS/MS methods for routine quantification of targeted steroids and cannabinoids, respectively. The methods were developed using an isotopic approach, including validation for linearity, selectivity, LLOQ determination, matrix effect, carryover, between- and within-run accuracy and precision, and stability tests to measure 11 steroids and seven cannabinoids in human plasma. These methods were satisfactory for most validity conditions, although not all met the acceptance criteria for all analytes. A comparison of calibration curves in biological and surrogate matrices and in methanol showed that the latter condition was more applicable for our quantification of endogenous compounds. In conclusion, the validation of our methods met the criteria for GLP-qualified rather than GLP-validated methods, which can be used for routine analytical studies for dedicated preclinical and clinical purposes, by combining appropriate system suitability testing, including quality controls in the biological matrix. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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12 pages, 991 KiB

Open AccessArticle

Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder

by Verica Milivojevic, Lily Charron, Nia Fogelman, Gretchen Hermes and Rajita Sinha

Biomolecules 2022, 12(11), 1593; https://doi.org/10.3390/biom12111593 - 29 Oct 2022

Cited by 4 | Viewed by 2255

Abstract

Chronic cocaine use leads to adaptations in stress biology and in neuroactive steroid system. These adaptations are associated with high cocaine craving and increased relapse risk. This study tested whether potentiation of the neuroactive steroid system with the precursor pregnenolone (PREG) affects stress- and cue-induced cocaine craving, anxiety and autonomic response in individuals with cocaine use disorder (CUD). Thirty treatment-seeking individuals (21 Male, 9 Female) with CUD were randomized to placebo (PBO) or supraphysiologic PREG doses of 300 mg or 500 mg per day for 8 weeks. After 2 weeks of treatment, participants were exposed to 5-min personalized guided imagery provocation of stress, cocaine, or neutral/relaxing cues in a 3-day experiment, one condition per day on separate days, in a random, counterbalanced order. Repeated assessment of cocaine craving, anxiety, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were assessed on each day. PREG significantly increased pregnenolone levels compared to PBO. Both PREG doses decreased stress- and cocaine cue-induced craving and reduced both stress- and cue-induced anxiety only in the 500 mg/day group. The 500 mg/day PREG group also displayed decreased stress-induced HR, SBP and DBP. Findings indicate that pregnenolone decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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15 pages, 1597 KiB

Open AccessEditor’s ChoiceArticle

Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats

by Silvia Diviccaro, Silvia Giatti, Lucia Cioffi, Eva Falvo, Monika Herian, Donatella Caruso and Roberto Cosimo Melcangi

Biomolecules 2022, 12(11), 1567; https://doi.org/10.3390/biom12111567 - 26 Oct 2022

Cited by 5 | Viewed by 8350

Abstract

The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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20 pages, 1624 KiB

Open AccessEditor’s ChoiceArticle

(3α,5α)3-Hydroxypregnan-20-one (3α,5α-THP) Regulation of the HPA Axis in the Context of Different Stressors and Sex

by Giorgia Boero, Ryan E. Tyler, Todd K. O’Buckley, Irina Balan, Joyce Besheer and A. Leslie Morrow

Biomolecules 2022, 12(8), 1134; https://doi.org/10.3390/biom12081134 - 18 Aug 2022

Cited by 8 | Viewed by 1420

Abstract

Corticotropin-releasing factor (CRF) regulates the stress response in the hypothalamus and modulates neurotransmission across the brain through CRF receptors. Acute stress increases hypothalamic CRF and the GABAergic neurosteroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP). We previously showed that 3α,5α-THP regulation of CRF is sex and brain region dependent. In this study, we investigated 3α,5α-THP regulation of stress-induced hypothalamic CRF, CRF receptor type 1 (CRFR1), CRF binding protein (CRFBP), pro-opiomelanocortin (POMC), and glucocorticoid receptor (GR) by western blot and circulating corticosterone (CORT) by enzyme-linked immunosorbent assay (ELISA) in male and female Sprague Dawley rats. Tissue was collected after rats were injected with 3α,5α-THP (15 mg/kg, IP) or vehicle 15 min prior to 30 min of restraint stress (RS), or 10 min of forced swim stress (FSS) and 20 min recovery. The initial exposure to a stress stimulus increased circulating CORT levels in both males and females, but 3α,5α-THP attenuated the CORT response only in females after RS. 3α,5α-THP reduced GR levels in male and females, but differently between stressors. 3α,5α-THP decreased the CRF stress response after FSS in males and females, but after RS, only in female rats. 3α,5α-THP reduced the CRFR1, CRFBP, and POMC increases after RS and FSS in males, but in females only after FSS. Our results showed different stress responses following different types of stressors: 3α,5α-THP regulated the HPA axis at different levels, depending on sex. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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21 pages, 3901 KiB

Open AccessArticle

Gut Steroids and Microbiota: Effect of Gonadectomy and Sex

by Silvia Diviccaro, Jamie A. FitzGerald, Lucia Cioffi, Eva Falvo, Fiona Crispie, Paul D. Cotter, Siobhain M. O’Mahony, Silvia Giatti, Donatella Caruso and Roberto Cosimo Melcangi

Biomolecules 2022, 12(6), 767; https://doi.org/10.3390/biom12060767 - 31 May 2022

Cited by 11 | Viewed by 2779

Abstract

Sex steroids, derived mainly from gonads, can shape microbiota composition; however, the impact of gonadectomy and sex on steroid production in the gut (i.e., gut steroids), and its interaction with microbiota composition, needs to be clarified. In this study, steroid environment and gut steroidogenesis were analysed by liquid chromatography tandem mass spectrometry and expression analyses. Gut microbiota composition as branched- and short-chain fatty acids were determined by 16S rRNA gene sequence analysis and gas chromatography flame ionisation detection, respectively. Here, we first demonstrated that levels of pregnenolone (PREG), progesterone (PROG), and isoallopregnanolone (ISOALLO) were higher in the female rat colon, whereas the level of testosterone (T) was higher in males. Sexual dimorphism on gut steroidogenesis is also reported after gonadectomy. Sex, and more significantly, gonadectomy, affects microbiota composition. We noted that a number of taxa and inferred metabolic pathways were associated with gut steroids, such as positive associations between Blautia with T, dihydroprogesterone (DHP), and allopregnanolone (ALLO), whereas negative associations were noted between Roseburia and T, ALLO, PREG, ISOALLO, DHP, and PROG. In conclusion, this study highlights the novel sex-specific association between microbiota and gut steroids with possible relevance for the gut-brain axis. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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Review

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15 pages, 788 KiB

Open AccessFeature PaperReview

The Allopregnanolone Response to Acute Stress in Females: Preclinical and Clinical Studies

by Maria Giuseppina Pisu, Luca Concas, Carlotta Siddi, Mariangela Serra and Patrizia Porcu

Biomolecules 2022, 12(9), 1262; https://doi.org/10.3390/biom12091262 - 08 Sep 2022

Cited by 3 | Viewed by 2038

Abstract

The neuroactive steroid allopregnanolone ((3α,5α)-3-hydroxypregnan-20-one or 3α,5α-THP) plays a key role in the response to stress, by normalizing hypothalamic-pituitary-adrenal (HPA) axis function to restore homeostasis. Most studies have been conducted on male rats, and little is known about the allopregnanolone response to stress in females, despite that women are more susceptible than men to develop emotional and stress-related disorders. Here, we provide an overview of animal and human studies examining the allopregnanolone responses to acute stress in females in the context of stress-related neuropsychiatric diseases and under the different conditions that characterize the female lifespan associated with the reproductive function. The blunted allopregnanolone response to acute stress, often observed in female rats and women, may represent one of the mechanisms that contribute to the increased vulnerability to stress and affective disorders in women under the different hormonal fluctuations that occur throughout their lifespan. These studies highlight the importance of targeting neuroactive steroids as a therapeutic approach for stress-related disorders in women. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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