No abstract

We have previously shown that progesterone (PROG) is synthesized by Schwann cells and promotes myelin formation in the peripheral nervous system (PNS). We now report that this neurosteroid also stimulates myelination in organotypic slice cultures of 7-day-old (P7) rat and mouse cerebellum. Myelination was evaluated by immunofluorescence analysis of the myelin basic protein (MBP). After 7 days in culture (7DIV), we found that adding PROG (2-5 · 10 )5 M) to the culture medium caused a fourfold increase in MBP expression when compared to control slices. The effect of PROG on MBP expression involves the classical intracellular PROG receptor (PR): the selective PR agonist R5020 significantly increased MBP expression and the PR antagonist mifepristone (RU486) completely abolished the effect of PROG on this MBP expression. Moreover, treatment of P7-cerebellar slice cultures from PR knockout (PRKO) mice with PROG had no significant effect on MBP expression. PROG was metabolized in the cerebellar slices to 5a-dihydroprogesterone (5a-DHP) and to the GABA A receptor-active metabolite 3a,5a-tetrahydroprogesterone (3a,5a-THP, allopregnanolone). The 5a-reductase inhibitor L685-273 partially inhibited the effect of PROG, and 3a,5a-THP (2-5 · 10 )5 M) significantly stimulated the MBP expression, although to a lesser extent than PROG. The increase in MBP expression by 3a,5a-THP involved GABA A receptors, as it could be inhibited by the selective GABA A receptor antagonist bicuculline. These findings suggest that progestins stimulate MBP expression and consequently suggest an increase in CNS myelination via two signalling systems, the intracellular PR and membrane GABA A receptors, and they confirm a new role of GABA A receptors in myelination.

No abstract

The utility and safety of postmenopausal hormone replacement therapy has recently been put into question by large clinical trials. Their outcome has been extensively commented upon, but discussions have mainly been limited to the effects of estrogens. In fact, progestagens are generally only considered with respect to their usefulness in preventing estrogen stimulation of uterine hyperplasia and malignancy. In addition, various risks have been attributed to progestagens and their omission from hormone replacement therapy has been considered, but this may underestimate their potential benefits and therapeutic promises. A major reason for the controversial reputation of progestagens is that they are generally considered as a single class. Moreover, the term progesterone is often used as a generic one for the different types of both natural and synthetic progestagens. This is not appropriate because natural progesterone has properties very distinct from the synthetic progestins. Within the nervous system, the neuroprotective and promyelinating effects of progesterone are promising, not only for preventing but also for reversing age-dependent changes and dysfunctions. There is indeed strong evidence that the aging nervous system remains at least to some extent sensitive to these beneficial effects of progesterone. The actions of progesterone in peripheral target tissues including breast, blood vessels, and bones are less well understood, but there is evidence for the beneficial effects of progesterone. The variety of signaling mechanisms of progesterone offers exciting possibilities for the development of more selective, efficient, and safe progestagens. The recognition that progesterone is synthesized by neurons and glial cells requires a reevaluation of hormonal aging.