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

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

doi:10.3390/ijms21093163

Narimène Asbelaoui, Charly Abi Ghanem + Show 3 more

Open Access

https://doi.org/10.3390/ijms21093163

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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.

Highlights

As numerous experimental animal studies have demonstrated an important role of progesterone and testosterone, among other steroid hormones, in the processes of myelination and remyelination (Figure 1B), we focus this review on updated data from our group and others that begin to identify and characterize the roles of these two steroids and their respective nuclear receptor (NR) signaling in myelin development and repair
The nervous system, in addition to be a target for steroid hormones, is the source of a variety of neuroactive steroids, which are synthesized and metabolized by glial cells and neurons
Several studies including ours convincingly show that progesterone and testosterone play a key role in the process of myelination and remyelination

Summary

Myelinating Cells of the Central Nervous System

The central nervous system (CNS) can be distinguished into two major regions: grey and white matter. Each category is morphologically distinct; OPCs are bipolar, migratory in nature and proliferative cells while mature oligodendrocytes are highly branched cells specialized to make myelin sheets. They lack the capacity for proliferation and migration. Intercellular connections between astrocytes and oligodendrocytes are vital for the proper functioning of oligodendrocytes They produce several growth factors, such as platelet-derived growth factor, brain-derived neurotrophic factor or ciliary neurotrophic factor to promote OPC development and CNS myelination and they aid in the removal of myelin debris [20,21,22,23,24,25]. See review by Traiffort et al, 2020) [33]

Myelination

Remyelination

Steroid Hormones and Their Nuclear Receptor Signaling Mechanisms

In Vitro Studies

Androgen Receptor’s Functions

In Vitro and In Vivo Translational Studies and Clinical Trials

Findings

Conclusions