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Role of Neuroactive Steroids in Health and Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 February 2024) | Viewed by 11297

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Prof. Dr. Roberto Cosimo Melcangi

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Dipartimento di Scienze Farmacologiche e Biomolecolari “Rodolfo Paoletti”, Università degli Studi di Milano, Milano, Italy
Interests: neuroactive steroids; neurosteroids; neuroprotection; neurodegenerative disorders; psychiatric disorders; sex differences
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Dear Colleagues,

The term “neuroactive steroids” has been coined to indicate steroids modulating brain functions, independently of their origin. Thus, neurosteroids (i.e., steroids directly synthesized in the nervous system) and steroid hormones (i.e., molecules synthesized in gonadal and adrenal glands) are included in this family. These molecules, by classical and/or non-classical steroid receptors, act as important physiological regulators of the nervous functions (e.g., regulation of memory, learning, myelination, reproductive behavior and glial functions), as well as neuroprotective agents in neurodegenerative (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, traumatic brain injury, stroke, peripheral neuropathies) and psychiatric (depression, anxiety, posttraumatic stress, etc.) disorders. This Special Issue will collect original articles and reviews highlighting the fundamental physiological and pathological roles of these molecules.

Prof. Dr. Roberto Cosimo Melcangi
Guest Editor

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Keywords

neurosteroids
neurodegenerative disorders
psychiatric disorders
physiological effects

Related Special Issue

Role of Neuroactive Steroids in Health and Disease, 2nd Volume in Biomolecules

Published Papers (10 papers)

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Research

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22 pages, 3397 KiB

Open AccessArticle

Neurosteroid Modulation of Synaptic and Extrasynaptic GABA_A Receptors of the Mouse Nucleus Accumbens

by Scott J. Mitchell, Grant D. Phillips, Becks Tench, Yunkai Li, Delia Belelli, Stephen J. Martin, Jerome D. Swinny, Louise Kelly, John R. Atack, Michael Paradowski and Jeremy J. Lambert

Biomolecules 2024, 14(4), 460; https://doi.org/10.3390/biom14040460 - 9 Apr 2024

Viewed by 728

Abstract

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABA_AR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABA_ARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABA_ARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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25 pages, 11422 KiB

Open AccessArticle

Testosterone Reduces Myelin Abnormalities in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis

by Ivan J. Esperante, Maria Meyer, Carolina Banzan, Maria Sol Kruse, Analia Lima, Paulina Roig, Rachida Guennoun, Michael Schumacher, Alejandro F. De Nicola and Maria Claudia Gonzalez Deniselle

Biomolecules 2024, 14(4), 428; https://doi.org/10.3390/biom14040428 - 1 Apr 2024

Viewed by 678

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron degenerative disease that is associated with demyelination. The Wobbler (WR) mouse exhibits motoneuron degeneration, gliosis and myelin deterioration in the cervical spinal cord. Since male WRs display low testosterone (T) levels in the nervous system, we investigated if T modified myelin-relative parameters in WRs in the absence or presence of the aromatase inhibitor, anastrozole (A). We studied myelin by using luxol-fast-blue (LFB) staining, semithin sections, electron microscopy and myelin protein expression, density of IBA1⁺ microglia and mRNA expression of inflammatory factors, and the glutamatergic parameters glutamine synthetase (GS) and the transporter GLT1. Controls and WR + T showed higher LFB, MBP and PLP staining, lower g-ratios and compact myelin than WRs and WR + T + A, and groups showing the rupture of myelin lamellae. WRs showed increased IBA1⁺ cells and mRNA for CD11b and inflammatory factors (IL-18, TLR4, TNFαR₁ and P₂Y₁₂R) vs. controls or WR + T. IBA1⁺ cells, and CD11b were not reduced in WR + T + A, but inflammatory factors’ mRNA remained low. A reduction of GS⁺ cells and GLT-1 immunoreactivity was observed in WRs and WR + T + A vs. controls and WR + T. Clinically, WR + T but not WR + T + A showed enhanced muscle mass, grip strength and reduced paw abnormalities. Therefore, T effects involve myelin protection, a finding of potential clinical translation. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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12 pages, 2127 KiB

Open AccessArticle

Dissecting the Long-Term Effect of Stress Early in Life on FKBP5: The Role of miR-20b-5p and miR-29c-3p

by Nadia Cattane, Maria Grazia Di Benedetto, Ilari D’Aprile, Marco Andrea Riva and Annamaria Cattaneo

Biomolecules 2024, 14(3), 371; https://doi.org/10.3390/biom14030371 - 19 Mar 2024

Viewed by 681

Abstract

Exposure to early-life stress (ELS) has been related to an increased susceptibility to psychiatric disorders later in life. Although the molecular mechanisms underlying this association are still under investigation, glucocorticoid signaling has been proposed to be a key mediator. Here, we used two preclinical models, the prenatal stress (PNS) animal model and an in vitro model of hippocampal progenitor cells, to assess the long-term effect of ELS on FKBP5, NR3C1, NR3C2, and FoxO1, four stress-responsive genes involved in the effects of glucocorticoids. In the hippocampus of male PNS rats sacrificed at different time points during neurodevelopment (PND 21, 40, 62), we found a statistically significant up-regulation of FKBP5 at PND 40 and PND 62 and a significant increase in FoxO1 at PND 62. Interestingly, all four genes were significantly up-regulated in differentiated cells treated with cortisol during cell proliferation. As FKBP5 was consistently modulated by PNS at adolescence (PND 40) and adulthood (PND 62) and by cortisol treatment after cell differentiation, we measured a panel of miRNAs targeting FKBP5 in the same samples where FKBP5 expression levels were available. Interestingly, both miR-20b-5p and miR-29c-3p were significantly reduced in PNS-exposed animals (both at PND40 and 62) and also in the in vitro model after cortisol exposure. Our results highlight the key role of miR-20b-5p and miR-29c-3p in sustaining the long-term effects of ELS on the stress response system, representing a mechanistic link possibly contributing to the enhanced stress-related vulnerability to mental disorders. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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18 pages, 2874 KiB

Open AccessArticle

Effects of Complete and Partial Loss of the 24S-Hydroxycholesterol-Generating Enzyme Cyp46a1 on Behavior and Hippocampal Transcription in Mouse

by Hong-Jin Shu, Luke H. Ziolkowski, Sofia V. Salvatore, Ann M. Benz, David F. Wozniak, Carla M. Yuede, Steven M. Paul, Charles F. Zorumski and Steven Mennerick

Biomolecules 2024, 14(3), 254; https://doi.org/10.3390/biom14030254 - 21 Feb 2024

Viewed by 767

Abstract

Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally dependent transcriptional effects on select cholesterol metabolism genes. These included paradoxical changes in Liver X Receptor targets. Again, conditional knockout was insufficient to recapitulate most changes. Overall, our results highlight the complex effects of 24S-HC in an in vivo setting that are not fully predicted by known mechanisms. The results also demonstrate that the complete inhibition of enzymatic activity may be needed for a detectable, therapeutically relevant impact on gene expression and behavior. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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18 pages, 3301 KiB

Open AccessArticle

Steroid Metabolomic Signature in Term and Preterm Infants

by Matthias Heckmann, Anna S. Runkel, Donna E. Sunny, Michaela F. Hartmann, Till Ittermann and Stefan A. Wudy

Biomolecules 2024, 14(2), 235; https://doi.org/10.3390/biom14020235 - 17 Feb 2024

Viewed by 829

Abstract

Adrenal function is essential for survival and well-being of preterm babies. In addition to glucocorticoids, it has been hypothesized that C₁₉-steroids (DHEA-metabolites) from the fetal zone of the adrenal gland may play a role as endogenous neuroprotective steroids. In 39 term-born (≥37 weeks gestational age), 42 preterm (30–36 weeks) and 51 early preterm (<30 weeks) infants 38 steroid metabolites were quantified by GC-MS in 24-h urinary samples. In each gestational age group, three distinctive cluster were identified by pattern analysis (k-means clustering). Individual steroidal fingerprints and clinical phenotype were analyzed at the 3rd day of life. Overall, the excretion rates of C₂₁-steroids (glucocorticoid precursors, cortisol, and cortisone metabolites) were low (<99 μg/kg body weight/d) whereas the excretion rates of C₁₉-steroids were up to 10 times higher. There was a shift to higher excretion rates of C₁₉-steroids in both preterm groups compared to term infants but only minor differences in the distribution of C₂₁-steroids. Comparable metabolic patterns were found between gestational age groups: Cluster 1 showed mild elevation of C₂₁- and C₁₉-steroids with the highest incidence of neonatal morbidities in term and severe intraventricular hemorrhage in early preterm infants. In cluster 2 lowest excretion in general was noted but no clinically unique phenotype. Cluster 3 showed highest elevation of C₂₁-steroids and C₁₉-steroids but no clinically unique phenotype. Significant differences in steroid metabolism between clusters are only partly reflected by gestational age and disease severity. In early preterm infants, higher excretion rates of glucocorticoids and their precursors were associated with severe cerebral hemorrhage. High excretion rates of C₁₉-steroids in preterm infants may indicate a biological significance. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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21 pages, 3006 KiB

Open AccessEditor’s ChoiceArticle

Neuroactive Steroid–Gut Microbiota Interaction in T2DM Diabetic Encephalopathy

by Silvia Diviccaro, Lucia Cioffi, Rocco Piazza, Donatella Caruso, Roberto Cosimo Melcangi and Silvia Giatti

Biomolecules 2023, 13(9), 1325; https://doi.org/10.3390/biom13091325 - 29 Aug 2023

Viewed by 1076

Abstract

The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography–tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dysfunction were reported. Interestingly, our analysis highlighted a small group of taxa strictly related to both memory impairment and neuroactive steroid levels. Overall, the data underline an interesting role for allopregnanolone and microbiota that may represent candidates for the development of therapeutic strategies. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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17 pages, 2885 KiB

Open AccessArticle

Isoallopregnanolone Inhibits Estrus Cycle-Dependent Aggressive Behavior

by Torbjörn Bäckström, Sara K. S. Bengtsson, Jessica Sjöstedt, Evgenya Malinina, Maja Johansson, Gianna Ragagnin, Karin Ekberg and Per Lundgren

Biomolecules 2023, 13(6), 1017; https://doi.org/10.3390/biom13061017 - 20 Jun 2023

Cited by 1 | Viewed by 1324

Abstract

Among female rats, some individuals show estrus cycle-dependent irritability/aggressive behaviors, and these individual rats may be used as a model for premenstrual dysphoric disorder (PMDD). We wanted to investigate if these behaviors are related to the estrus cycle phase containing moderately increased levels of positive GABA-A receptor-modulating steroids (steroid-PAM), especially allopregnanolone (ALLO), and if the adverse behavior can be antagonized. The electrophysiology studies in this paper show that isoallopregnanolone (ISO) is a GABA-A-modulating steroid antagonist (GAMSA), meaning that ISO can antagonize the agonistic effects of positive GABA-A receptor-modulating steroids in both α1β2γ2L and α4β3δ GABA-A receptor subtypes. In this study, we also investigated whether ISO could antagonize the estrus cycle-dependent aggressive behaviors in female Wistar rats using a resident–intruder test. Our results confirmed previous reports of estrus cycle-dependent behaviors in that 42% of the tested rats showed higher levels of irritability/aggression at diestrus compared to those at estrus. Furthermore, we found that, during the treatment with ISO, the aggressive behavior at diestrus was alleviated to a level comparable to that of estrus. We noticed an 89% reduction in the increase in aggressive behavior at diestrus compared to that at estrus. Vehicle treatment in the same animals showed a minimal effect on the diestrus-related aggressive behavior. In conclusion, we showed that ISO can antagonize Steroid-PAM both in α1β2γ2L and α4β3δ GABA-A receptor subtypes and inhibit estrus cycle-dependent aggressive behavior. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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18 pages, 9916 KiB

Open AccessArticle

Sex and Age Differences in a Progressive Synucleinopathy Mouse Model

by Jérôme Lamontagne-Proulx, Katherine Coulombe, Marc Morissette, Marie Rieux, Frédéric Calon, Thérèse Di Paolo and Denis Soulet

Biomolecules 2023, 13(6), 977; https://doi.org/10.3390/biom13060977 - 11 Jun 2023

Cited by 4 | Viewed by 1417

Abstract

The mutation and overexpression of the alpha-synuclein protein (αSyn), described as synucleinopathy, is associated with Parkinson’s disease (PD)-like pathologies. A higher prevalence of PD is documented for men versus women, suggesting female hormones’ implication in slowing PD progression. The nigrostriatal dopamine (DA) neurons in rodent males are more vulnerable to toxins than those in females. The effect of biological sex on synucleinopathy remains poorly described and was investigated using mice knocked out for murine αSyn (SNCA-/-) and also overexpressing human αSyn (SNCA-OVX) compared to wildtype (WT) mice. All the mice showed decreased locomotor activity with age, and more abruptly in the male than in the female SNCA-OVX mice; anxiety-like behavior increased with age. The SNCA-OVX mice had an age-dependent accumulation of αSyn. Older age was associated with the loss of nigral DA neurons and decreased striatal DA contents. The astrogliosis, microgliosis, and cytokine concentrations increased with aging. More abrupt nigrostriatal DA decreases and increased microgliosis were observed in the male SNCA-OVX mice. Human αSyn overexpression and murine αSyn knockout resulted in behavioral dysfunctions, while only human αSyn overexpression was toxic to DA neurons. At 18 months, neuroprotection was lost in the female SNCA-OVX mice, with a likely loss of estrus cycles. In conclusion, sex-dependent αSyn toxicity was observed, affecting the male mice more significantly. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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Review

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12 pages, 488 KiB

Open AccessReview

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

by Vesna Jevtovic-Todorovic and Slobodan M. Todorovic

Biomolecules 2023, 13(11), 1654; https://doi.org/10.3390/biom13111654 - 15 Nov 2023

Viewed by 1085

Abstract

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. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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15 pages, 742 KiB

Open AccessReview

Repurposing of Tibolone in Alzheimer’s Disease

by George E. Barreto

Biomolecules 2023, 13(7), 1115; https://doi.org/10.3390/biom13071115 - 13 Jul 2023

Cited by 1 | Viewed by 1934

Abstract

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterised by the accumulation of amyloid-beta and tau in the brain, leading to the progressive loss of memory and cognition. The causes of its pathogenesis are still not fully understood, but some risk factors, such as age, genetics, and hormones, may play a crucial role. Studies show that postmenopausal women have a higher risk of developing AD, possibly due to the decrease in hormone levels, especially oestrogen, which may be directly related to a reduction in the activity of oestrogen receptors, especially beta (ERβ), which favours a more hostile cellular environment, leading to mitochondrial dysfunction, mainly affecting key processes related to transport, metabolism, and oxidative phosphorylation. Given the influence of hormones on biological processes at the mitochondrial level, hormone therapies are of clinical interest to reduce the risk or delay the onset of symptoms associated with AD. One drug with such potential is tibolone, which is used in clinics to treat menopause-related symptoms. It can reduce amyloid burden and have benefits on mitochondrial integrity and dynamics. Many of its protective effects are mediated through steroid receptors and may also be related to neuroglobin, whose elevated levels have been shown to protect against neurological diseases. Its importance has increased exponentially due to its implication in the pathogenesis of AD. In this review, we discuss recent advances in tibolone, focusing on its mitochondrial-protective effects, and highlight how valuable this compound could be as a therapeutic alternative to mitigate the molecular pathways characteristic of AD. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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