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Steroids and the Nervous System

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 47255

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Dr. Rachida Guennoun

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Guest Editor

U1195 Inserm and University Paris-Sud and University Paris Saclay 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France
Interests: steroids; neurosteroids; neuroprotection; stroke

Special Issue Information

Dear Colleagues,

Steroids have pleiotropic effects on the nervous system (NS) throughout the lifespan. The NS is both a target and a site of synthesis and metabolism of steroids. Steroid concentrations in the NS depend both on systemic intake and local synthesis. It is now well established that the NS is able to synthesize progesterone, testosterone, and estradiol from cholesterol. In addition, steroids can be metabolized in the NS, and the resulting metabolites can be active agents In different models of NS lesion and neurodegenerative diseases, changes in the local endogenous steroid levels have been observed, suggesting that steroids have an important role in pathophysiological conditions. In addition, several pharmacological studies have demonstrated the therapeutic potential of estrogens, progestagens, and androgens.

This Special Issue “Steroids and the Nervous System” will compile reviews that address various aspects of the relationships between steroids and the NS, including synthesis, metabolism, regulation, and effects. Special emphasis will be on neurosteroids, neuroactive steroids, and the effects of steroids on brain development and sexual differentiation, neuroprotection, neuroinflammation, myelination, synaptic modulation, memory, and behavior. Reviews on the therapeutic potential of steroids for NS injuries and disorders are also welcome.

Dr. Rachida Guennoun
Guest Editor

Manuscript Submission Information

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Keywords

Steroids
Neurosteroids
Neuroactive steroids
Neuroprotection
Myelination
Neuroinflammation
Sexual differentiation
Synaptic modulation
Memory

Published Papers (7 papers)

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Research

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21 pages, 3977 KiB

Open AccessArticle

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

by Claudia Espinosa-Garcia, Fahim Atif, Seema Yousuf, Iqbal Sayeed, Gretchen N. Neigh and Donald G. Stein

Int. J. Mol. Sci. 2020, 21(11), 3740; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113740 - 26 May 2020

Cited by 36 | Viewed by 3986

Abstract

NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions. Full article

(This article belongs to the Special Issue Steroids and the Nervous System)

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Review

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21 pages, 1074 KiB

Open AccessReview

Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

by Rachida Guennoun

Int. J. Mol. Sci. 2020, 21(15), 5271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155271 - 24 Jul 2020

Cited by 71 | Viewed by 9968

Abstract

Progesterone has a broad spectrum of actions in the brain. Among these, the neuroprotective effects are well documented. Progesterone neural effects are mediated by multiple signaling pathways involving binding to specific receptors (intracellular progesterone receptors (PR); membrane-associated progesterone receptor membrane component 1 (PGRMC1); and membrane progesterone receptors (mPRs)) and local bioconversion to 3α,5α-tetrahydroprogesterone (3α,5α-THPROG), which modulates GABA_A receptors. This brief review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain. First, we succinctly describe the biosynthetic pathways and the expression of enzymes and receptors of progesterone; as well as the changes observed after brain injuries and in neurological diseases. Then, we summarize current data on the differential fluctuations in brain levels of progesterone and its neuroactive metabolites according to sex, age, and neuropathological conditions. The third part is devoted to the neuroprotective effects of progesterone and 3α,5α-THPROG in different experimental models, with a focus on traumatic brain injury and stroke. Finally, we highlight the key role of the classical progesterone receptors (PR) in mediating the neuroprotective effects of progesterone after stroke. Full article

(This article belongs to the Special Issue Steroids and the Nervous System)

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29 pages, 2859 KiB

Open AccessReview

Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential

by Yvette Akwa

Int. J. Mol. Sci. 2020, 21(13), 4812; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134812 - 07 Jul 2020

Cited by 31 | Viewed by 6524

Abstract

Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that they exhibit pleiotropic neuroprotective properties that are relevant for AD. This review focuses on the relationship between selected neuroactive steroids and the main aspects of AD disease, pointing out contributions and gaps with reference to sex differences. We take into account the regulation of brain steroid concentrations associated with human AD pathology. Consideration is given to preclinical studies in AD models providing current knowledge on the neuroprotection offered by neuroactive (neuro)steroids on major AD pathogenic factors, such as amyloid-β (Aβ) and tau pathology, mitochondrial impairment, neuroinflammation, neurogenesis and memory loss. Stimulating endogenous steroid production opens a new steroid-based strategy to potentially overcome AD pathology. This article is part of a Special Issue entitled Steroids and the Nervous System. Full article

(This article belongs to the Special Issue Steroids and the Nervous System)

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23 pages, 2134 KiB

Open AccessReview

De Novo Synthesized Estradiol: A Role in Modulating the Cerebellar Function

by Cristina V. Dieni, Samuele Contemori, Andrea Biscarini and Roberto Panichi

Int. J. Mol. Sci. 2020, 21(9), 3316; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093316 - 07 May 2020

Cited by 16 | Viewed by 9972

Abstract

The estrogen estradiol is a potent neuroactive steroid that may regulate brain structure and function. Although the effects of estradiol have been historically associated with gonadal secretion, the discovery that this steroid may be synthesized within the brain has expanded this traditional concept. Indeed, it is accepted that de novo synthesized estradiol in the nervous system (nE2) may modulate several aspects of neuronal physiology, including synaptic transmission and plasticity, thereby influencing a variety of behaviors. These modulations may be on a time scale of minutes via non-classical and often membrane-initiated mechanisms or hours and days by classical actions on gene transcription. Besides the high level, recent investigations in the cerebellum indicate that even a low aromatase expression can be related to the fast nE2 effect on brain functioning. These pieces of evidence point to the importance of an on-demand and localized nE2 synthesis to rapidly contribute to regulating the synaptic transmission. This review is geared at exploring a new scenario for the impact of estradiol on brain processes as it emerges from the nE2 action on cerebellar neurotransmission and cerebellum-dependent learning. Full article

(This article belongs to the Special Issue Steroids and the Nervous System)

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24 pages, 2170 KiB

Open AccessReview

Microglial and Astrocytic Function in Physiological and Pathological Conditions: Estrogenic Modulation

by Andrea Crespo-Castrillo and Maria-Angeles Arevalo

Int. J. Mol. Sci. 2020, 21(9), 3219; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093219 - 02 May 2020

Cited by 29 | Viewed by 6512

Abstract

There are sexual differences in the onset, prevalence, and outcome of numerous neurological diseases. Thus, in Alzheimer’s disease, multiple sclerosis, and major depression disorder, the incidence in women is higher than in men. In contrast, men are more likely to present other pathologies, such as amyotrophic lateral sclerosis, Parkinson’s disease, and autism spectrum. Although the neurological contribution to these diseases has classically always been studied, the truth is that neurons are not the only cells to be affected, and there are other cells, such as glial cells, that are also involved and could be key to understanding the development of these pathologies. Sexual differences exist not only in pathology but also in physiological processes, which shows how cells are differentially regulated in males and females. One of the reasons these sexual differences may occur could be due to the different action of sex hormones. Many studies have shown an increase in aromatase levels in the brain, which could indicate the main role of estrogens in modulating proinflammatory processes. This review will highlight data about sex differences in glial physiology and how estrogenic compounds, such as estradiol and tibolone, could be used as treatment in neurological diseases due to their anti-inflammatory effects and the ability to modulate glial cell functions. Full article

(This article belongs to the Special Issue Steroids and the Nervous System)

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18 pages, 1141 KiB

Open AccessReview

Roles of Progesterone, Testosterone and Their Nuclear Receptors in Central Nervous System Myelination and Remyelination

by Abdel Mouman Ghoumari, Charly Abi Ghanem, Narimène Asbelaoui, Michael Schumacher and Rashad Hussain

Int. J. Mol. Sci. 2020, 21(9), 3163; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093163 - 30 Apr 2020

Cited by 32 | Viewed by 5555

Abstract

Progesterone and testosterone, beyond their roles as sex hormones, are neuroactive steroids, playing crucial regulatory functions within the nervous system. Among these, neuroprotection and myelin regeneration are important ones. The present review aims to discuss the stimulatory effects of progesterone and testosterone on the process of myelination and remyelination. These effects have been demonstrated in vitro (i.e., organotypic cultures) and in vivo (cuprizone- or lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE)). Both steroids stimulate myelin formation and regeneration by acting through their respective intracellular receptors: progesterone receptors (PR) and androgen receptors (AR). Activation of these receptors results in multiple events involving direct transcription and translation, regulating general homeostasis, cell proliferation, differentiation, growth and myelination. It also ameliorates immune response as seen in the EAE model, resulting in a significant decrease in inflammation leading to a fast recovery. Although natural progesterone and testosterone have a therapeutic potential, their synthetic derivatives—the 19-norprogesterone (nestorone) and 7α-methyl-nortestosterone (MENT), already used as hormonal contraception or in postmenopausal hormone replacement therapies, may offer enhanced benefits for myelin repair. We summarize here a recent advancement in the field of myelin biology, to treat demyelinating disorders using the natural as well as synthetic analogs of progesterone and testosterone. Full article

(This article belongs to the Special Issue Steroids and the Nervous System)

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16 pages, 1377 KiB

Open AccessReview

Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases

by Alejandro F. De Nicola, Maria Meyer, Rachida Guennoun, Michael Schumacher, Hazel Hunt, Joseph Belanoff, E. Ronald de Kloet and Maria Claudia Gonzalez Deniselle

Int. J. Mol. Sci. 2020, 21(6), 2137; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062137 - 20 Mar 2020

Cited by 16 | Viewed by 3730

Abstract

Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic–pituitary–adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine–threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Steroids and the Nervous System)

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