Enhancing the endogenous capacity of myelin repair is a major therapeutic challenge in
demyelinating diseases such as
multiple sclerosis. We found that
progesterone and the synthetic
19-norprogesterone derivative 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione (
Nestorone) promote the remyelination of axons by oligodendrocytes after
lysolecithin-induced
demyelination in organotypic cultures of cerebellar slices taken from postnatal rats or mice. The intracellular
progesterone receptors (PR) mediate the proremyelinating actions of
Nestorone, because they are not observed in slices from PR knockout mice. Notably,
Nestorone was less efficient in heterozygous mice, expressing reduced levels of PR, suggesting PR haploinsufficiency in myelin repair. Using mice expressing the
enhanced green fluorescent protein (EGFP) under the control of the proteolipid gene promoter, we showed that both
progesterone and
Nestorone strongly increased the reappearance of cells of the oligodendroglial lineage in the demyelinated slices. In contrast to
Nestorone, the pregnane derivative
medroxyprogesterone acetate had no effect. The increase in oligodendroglial cells by
Nestorone resulted from enhanced NG2(+) and Olig2(+) oligodendrocyte progenitor cell (OPC) recruitment. In cocultures of
lysolecithin-demyelinated cerebellar slices from wild-type mice apposed to brain stem slices of proteolipid gene promoter-EGFP mice,
Nestorone stimulated the migration of OPC towards demyelinated axons. In this coculture paradigm,
Nestorone indeed markedly increased the number of EGFP(+) cells migrating into the demyelinated cerebellar slices. Our results show that
Nestorone stimulates the recruitment and maturation of OPC, two steps which are limiting for efficient myelin repair. They may thus open new perspectives for the use of
progestins, which selectively target PR, to promote the endogenous regeneration of myelin.