Steroid metabolism and effects in central and peripheral glial cells

Hormonal steroids participate in the control of a large number of functions of the central nervous system (CNS); recent data show that they may also intervene at the level of the peripheral nervous system (PNS). Both the CNS and the PNS metabolize endogenous as well as exogenous steroids; one of the major enzymatic system is represented by the 5alpha-reductase-3alpha-hydroxysteroid complex. This is a versatile system, since every steroid possessing the delta 4-3keto configuration (e.g., testosterone, progesterone, deoxycorticosterone) may be a substrate. High levels of 5alpha-reductase are found in the white matter of the CNS and in purified myelin. The observation that, in addition to neurons, glia may be a target for steroid action is an important recent finding. The effects of progesterone, testosterone, corticoids, and their respective 5alpha and 3alpha-5alpha derivatives on the expression of glial genes are presented and discussed. It has also been found that progesterone and/or its 5alpha-reduced metabolites increase the mRNA for the two major proteins of peripheral myelin, the glycoprotein Po and the peripheral myelin protein 22, in the sciatic nerve of normal and aged animals and in Schwann cells. The hypothesis has been put forward that glycoprotein Po might be under the control of progestagens acting mainly via the progesterone receptor, and that peripheral myelin protein 22 might be controlled via an interaction of steroids with the gamma-aminobutyric acid (GABA)ergic system. It is known that tetrahydroprogesterone, the 3alpha-5alpha-reduced metabolite of progesterone, interacts with the GABA(A) receptor. Our recent data show that several subunits of this receptor are present in sciatic nerve as well as in Schwann cells that reside in this nerve. These data open multiple possibilities for new therapeutic approaches to demyelinating diseases.