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Role of Neuroactive Steroids in Health and Disease: 2nd Edition
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Role of Neuroactive Steroids in Health and Disease: 2nd Edition

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

Deadline for manuscript submissions: 15 June 2025 | Viewed by 6548

Special Issue Editor

Prof. Dr. Roberto Cosimo Melcangi

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Following a very successful first run, we are pleased to announce the launch of a second edition of a Special Issue on the “Role of Neuroactive Steroids in Health and Disease, 2nd Volume”.

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, through classical and/or nonclassical steroid receptors, act as important physiological regulators of functions of the nervous system (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, post-traumatic stress, etc.) disorders. This Special Issue will collect original articles and reviews that highlight the fundamental physiological and pathological roles of these molecules.

Prof. Dr. Roberto Cosimo Melcangi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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
  • neurodegenerative disorders
  • psychiatric disorders
  • physiological effects

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Related Special Issue

Published Papers (5 papers)

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Research

19 pages, 999 KiB  
Article
Effects of Testosterone and Its Major Metabolites upon Different Stages of Neuron Survival in the Dentate Gyrus of Male Rats
by Mark D. Spritzer, Ethan A. Roy, Kelsey M. K. Calhoun, Zachary E. Schneider-Lynch, Leslie Panella, Charlotte Michaelcheck, April Qian, Evan D. Kelly, Hadley Barr, Emma Hall, Blaine Cunningham, Hieu H. M. Nguyen, Dani Xu, Jennifer M. Barker and Liisa A. M. Galea
Biomolecules 2025, 15(4), 542; https://doi.org/10.3390/biom15040542 - 7 Apr 2025
Viewed by 823
Abstract
Testosterone has been shown to enhance hippocampal neurogenesis through increased cell survival, but which stages of new neuron development are influenced by testosterone remains unclear. Therefore, we tested the effects of sex steroids administered during three different periods after cell division in the [...] Read more.
Testosterone has been shown to enhance hippocampal neurogenesis through increased cell survival, but which stages of new neuron development are influenced by testosterone remains unclear. Therefore, we tested the effects of sex steroids administered during three different periods after cell division in the dentate gyrus of adult male rats to determine when they influence the survival of new neurons. Adult male rats were bilaterally castrated. After 7 days of recovery, a single injection of bromodeoxyuridine (BrdU) was given on the first day of the experiment (Day 0) to label actively dividing cells. All subjects received five consecutive days of hormone injections during one of three stages of new neuron development (days 1–5, 6–10, or 11–15) after BrdU labeling. Subjects were injected during these time periods with either testosterone propionate (0.250 or 0.500 mg/rat), dihydrotestosterone (0.250 or 0.500 mg/rat), or estradiol benzoate (1.0 or 10 µg/rat). All subjects were euthanized sixteen days later to assess the effects of these hormones on the number of BrdU-labeled cells. The high dose of testosterone caused a significant increase in the number of BrdU-labeled cells in the hippocampus compared to all other groups, with the strongest effect caused by later injections (11-15 days old). In contrast, neither DHT nor estradiol injections had any significant effects on number of BrdU-labeled cells. Fluorescent double-labeling and confocal microscopy reveal that the majority of BrdU-labeled cells were neurons. Our results add to past evidence that testosterone increases neurogenesis, but whether this involves an androgenic or estrogenic pathway remains unclear. Full article
(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)
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16 pages, 2746 KiB  
Article
Novel Inhibitory Actions of Neuroactive Steroid [3α,5α]-3-Hydroxypregnan-20-One on Toll-like Receptor 4-Dependent Neuroimmune Signaling
by Alejandro G. Lopez, Venkat R. Chirasani, Irina Balan, Todd K. O’Buckley, Makayla R. Adelman and A. Leslie Morrow
Biomolecules 2024, 14(11), 1441; https://doi.org/10.3390/biom14111441 - 13 Nov 2024
Viewed by 1420
Abstract
The endogenous neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) modulates inflammatory and neuroinflammatory signaling through toll-like receptors (TLRs) in human and mouse macrophages, human blood cells and alcohol-preferring (P) rat brains. Although it is recognized that 3α,5α-THP inhibits TLR4 activation by blocking interactions with MD2 and MyD88, [...] Read more.
The endogenous neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) modulates inflammatory and neuroinflammatory signaling through toll-like receptors (TLRs) in human and mouse macrophages, human blood cells and alcohol-preferring (P) rat brains. Although it is recognized that 3α,5α-THP inhibits TLR4 activation by blocking interactions with MD2 and MyD88, the comprehensive molecular mechanisms remain to be elucidated. This study explores additional TLR4 activation sites, including TIRAP binding to MyD88, which is pivotal for MyD88 myddosome formation, as well as LPS interactions with the TLR4:MD2 complex. Both male and female P rats (n = 8/group) received intraperitoneal administration of 3α,5α-THP (15 mg/kg; 30 min) or a vehicle control, and their hippocampi were analyzed using immunoprecipitation and immunoblotting techniques. 3α,5α-THP significantly reduces the levels of inflammatory mediators IL-1β and HMGB1, confirming its anti-inflammatory actions. We found that MyD88 binds to TLR4, IRAK4, IRAK1, and TIRAP. Notably, 3α,5α-THP significantly reduces MyD88-TIRAP binding (Males: −31 ± 9%, t-test, p < 0.005; Females: −53 ± 15%, t-test, p < 0.005), without altering MyD88 interactions with IRAK4 or IRAK1, or the baseline expression of these proteins. Additionally, molecular docking and molecular dynamic analysis revealed 3α,5α-THP binding sites on the TLR4:MD2 complex, targeting a hydrophobic pocket of MD2 usually occupied by Lipid A of LPS. Surface plasmon resonance (SPR) assays validated that 3α,5α-THP disrupts MD2 binding of Lipid A (Kd = 4.36 ± 5.7 μM) with an inhibition constant (Ki) of 4.5 ± 1.65 nM. These findings indicate that 3α,5α-THP inhibition of inflammatory mediator production involves blocking critical protein-lipid and protein-protein interactions at key sites of TLR4 activation, shedding light on its mechanisms of action and underscoring its therapeutic potential against TLR4-driven inflammation. Full article
(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)
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13 pages, 484 KiB  
Communication
Reduced Levels of Neurosteroids in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients
by Chiara Lucchi, Cecilia Simonini, Cecilia Rustichelli, Rossella Avallone, Elisabetta Zucchi, Ilaria Martinelli, Giuseppe Biagini and Jessica Mandrioli
Biomolecules 2024, 14(9), 1076; https://doi.org/10.3390/biom14091076 - 28 Aug 2024
Cited by 3 | Viewed by 1308
Abstract
Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on [...] Read more.
Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on motor neuron degeneration. This single-center case-control study included 37 patients with amyotrophic lateral sclerosis (ALS) and 28 healthy controls. Cerebrospinal fluid (CSF) neurosteroid levels were quantified using liquid chromatography–electrospray tandem mass spectrometry and compared between the two cohorts. Neurosteroid concentrations have been correlated with neuroinflammation and neurodegeneration biomarkers detected through an automated immunoassay, along with disease features and progression. Pregnenolone, progesterone, allopregnanolone, pregnanolone, and testosterone levels were significantly lower in ALS patients’ CSF compared to healthy controls. A significant inverse correlation was found between neurofilament and neurosteroid levels. Neurosteroid concentrations did not correlate with disease progression, phenotype, genotype, or survival prediction. Our study suggests the independence of the disease features and its progression, from the dysregulation of neurosteroids in ALS patients’ CSF. This neurosteroid reduction may relate to disease pathogenesis or be a consequence of disease-related processes, warranting further research. The inverse correlation between neurosteroids and neurofilament levels may indicate a failure of compensatory neuroprotective mechanisms against neurodegeneration. Full article
(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)
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12 pages, 1729 KiB  
Article
Neurosteroid Levels in GBA Mutated and Non-Mutated Parkinson’s Disease: A Possible Factor Influencing Clinical Phenotype?
by Francesco Cavallieri, Chiara Lucchi, Sara Grisanti, Edoardo Monfrini, Valentina Fioravanti, Giulia Toschi, Giulia Di Rauso, Jessica Rossi, Alessio Di Fonzo, Giuseppe Biagini and Franco Valzania
Biomolecules 2024, 14(8), 1022; https://doi.org/10.3390/biom14081022 - 17 Aug 2024
Cited by 2 | Viewed by 1198
Abstract
Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids’ serum levels in a cohort of Parkinson’s Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects [...] Read more.
Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids’ serum levels in a cohort of Parkinson’s Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher’s exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn’s test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention. Full article
(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)
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21 pages, 7687 KiB  
Article
Alterations in the Hypothalamic–Pituitary–Adrenal Axis as a Response to Experimental Autoimmune Encephalomyelitis in Dark Agouti Rats of Both Sexes
by Ana Milosevic, Katarina Milosevic, Anica Zivkovic, Irena Lavrnja, Danijela Savic, Ivana Bjelobaba and Marija M. Janjic
Biomolecules 2024, 14(8), 1020; https://doi.org/10.3390/biom14081020 - 17 Aug 2024
Viewed by 1198
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine and endocrine systems. This study investigates the hypothalamic–pituitary–adrenal (HPA) axis response of male and female Dark Agouti rats during EAE. At the onset of EAE, Crh expression in the hypothalamus of both sexes is decreased, while males show reduced plasma adrenocorticotropic hormone levels. Adrenal gland activity is increased during EAE in both males and females, as evidenced by enlarged adrenal glands and increased StAR gene and protein expression. However, only male rats show increased serum and adrenal corticosterone levels, and an increased volume of the adrenal cortex. Adrenal 3β-HSD protein and progesterone levels are elevated in males only. Serum progesterone levels of male rats are also increased, although testicular progesterone levels are decreased during the disease, implying that the adrenal gland is the source of elevated serum progesterone levels in males. Our results demonstrate a sex difference in the response of the HPA axis at the adrenal level, with male rats showing a more pronounced induction during EAE. Full article
(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)
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