Progesterone and the nervous system
Michael Schumacher & Rachida Guennoun
The neuroprotective and promyelinating actions of progesterone, now well documented by experimental studies, make it a particularly promising therapeutic agent for neuroinjury. This concept has recently been translated into clinical practice. Progesterone can also be locally produced in the nervous system by neurons and glial cells. Importantly, increased progesterone synthesis after brain injury may be part of endogenous neuroprotective responses. However, the mechanisms by which progesterone exerts its actions in the nervous system are still not well understood, and its multiple signaling mechanisms present not only a challenge, but also opportunities for new therapeutic targeting. Mapping of the recently discovered membrane progesterone receptors in the central nervous system has revealed the wide distribution of their alpha isoform (mPRalpha), which is expressed in most populations of neurons, as well as in astrocytes, oligodendrocytes and neural progenitor cells. Interestingly, although mPRalpha binds natural progesterone with high affinity, it does not bind many of the synthetic progestins, which have been designed to target the classical intracellular progesterone receptors (PR). This is only one of the differences between the modes of action of natural progesterone and synthetic progestins, currently used in contraception or hormone replacement therapy. Thus, in contrast to progestins, progesterone is converted to its GABAA receptor-active metabolite allopregnanolone. While the membrane actions of progesterone need to be further explored, it should be emphasized that even PR-mediated non-reproductive functions of progesterone in the nervous system are still not well defined. Indeed, with the exception of their roles in reproduction, the significance of the widely distributed brain PR remains to be elucidated. Our recent experimental studies demonstrate a key role for PR in neuronal survival after cerebral ischemia. These findings suggest new therapeutic benefits for progestin ligands in the treatment of lesions and diseases of the nervous system.