Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex

El‐Etr, Martine; Rame, Marion; Boucher, Céline; Ghoumari, Abdel M.; Kumar, Narender; Lière, Philippe; Pianos, Antoine; Schumacher, Michaël; Sitruk-Ware, Régine

doi:10.1002/glia.22736

Cited by 97 publications

(67 citation statements)

References 71 publications

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“…Thus, an exercise-dependent increase in androgen biosynthesis within the hippocampus has been shown to stimulate neurogenesis (36). Other "neurosteroids" synthesized within the CNS, such as progesterone, may also positively influence the regeneration of CNS myelin (37,38). However, in our system, the effect of AR signaling was very robust and AR inactivation was not compensated for by other promyelinating signaling mechanisms.…”

Section: Discussionmentioning

confidence: 76%

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Bielecki

Mattern²,

Ghoumari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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101

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Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP) + and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0) + and peripheral myelin protein 22-kDa (PMP22) + myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-ketosteroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.T he remyelination of axons is a complex process, involving interactions between different types of neural cells. It shows a peculiarity that has been observed in both experimental models and demyelinating diseases such as multiple sclerosis (MS) (1). Although most of the remyelination is normally accomplished by oligodendrocytes derived from oligodendrocyte progenitors (OPs), a variable proportion of central nervous system (CNS) axons can be remyelinated by cells with the immunophenotypic and ultrastructural characteristics of Schwann cells, the presence of which is normally limited to the peripheral nervous system (PNS). These cells indeed express protein zero (P0), a sensitive and specific marker of Schwann cells (2). Moreover, analysis by electron microscopy demonstrated that they have the typical morphology of myelinating Schwann cells (1-4). These ultrastructural findings indicate that the expression of P0 by part of the remyelinating cells is not merely ectopic, but that these cells may correspond to authentic Schwann cells. This observation was further supported by their expression of Schwann cell-specific transcription factors (5).Importantly, there is strong evidence that large numbers of the Schwann cells present in demyelinating CNS lesions are derived from OPs. The first evidence came from the transplantation of purified OPs into demyelinating CNS lesions, in which endogenous ...

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Section: Discussionmentioning

confidence: 76%

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Bielecki

Mattern²,

Ghoumari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

101

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“…This allows the recovery of neurosteroidogenesis [64]. The re-myelinating effect of progesterone is dependent on the progesterone receptor [61].…”

Section: Progesterone and Progestinsmentioning

confidence: 99%

“…In contrast, Babri et al [60] reported that intrahippocampal injection of progesterone alone or in combination with vitamin C had no improving effects on memory. Progesterone and Nestorone also decrease neuroinflammatory responses, specifically astrocyte and microglial cell activation [61]. Therefore, some progestogens are promising therapeutic candidates for promoting the regeneration of myelin.…”

Section: Progesterone and Progestinsmentioning

confidence: 99%

The Role of Sex Hormones in Multiple Sclerosis

et al. 2018

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Multiple sclerosis (MS) is a chronic inflammatory demyelination disorder with an immune-mediated pathophysiology that affects the central nervous system (CNS). Like other autoimmune conditions, it has a predilection for female gender. This suggests a gender bias and a possible hormonal association. Inflammation and demyelination are hallmarks of MS. Oligodendrocytes are the myelinating cells of the CNS and these continue to be generated by oligodendrocyte precursor cells (OPCs). The process of remyelination represents a major form of plasticity in the developing adult CNS. Remyelination does occur in MS, but the process is largely inadequate and/or incomplete. Current treatment strategies primarily focus on reducing inflammation or immunosuppression, but there is a need for more extensive research on re-myelination as a possible mechanism of treatment. Previous studies have shown that pregnancy leads to an increase in OPC proliferation, oligodendrocyte generation and the number of myelinated axons in the maternal CNS. Studies have also suggested that this remyelination is possibly mediated by estriol. Sex hormones in particular have been shown to have an immuno-protective effect in TH1-driven autoimmunity diseases. The aim of our article is to review the available research on sex hormone-specific immune modulatory effects, assess its remyelination potential in MS, and suggest a future path for more extensive research on sex hormone as a target for therapeutics in MS.

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“…Progestogens, estrogens and androgens have indeed been shown to promote myelin regeneration in the CNS by stimulating the proliferation and differentiation of OPC and by promoting the synthesis of new myelin [9,[191][192][193][194][195]. In addition to their regenerative actions, CNS steroids exert protective effects on mature oligodendrocytes [196][197][198].…”

Section: Changes In Brain Steroid Levels In Response To Myelin Degenementioning

confidence: 99%

Analytical challenges for measuring steroid responses to stress, neurodegeneration and injury in the central nervous system

Schumacher

Guennoun

Mattern³

et al. 2015

Steroids

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Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex

Cited by 97 publications

References 71 publications

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

The Role of Sex Hormones in Multiple Sclerosis

Analytical challenges for measuring steroid responses to stress, neurodegeneration and injury in the central nervous system

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