NEUROSTEROIDS - A NEW FUNCTION IN THE BRAIN

Neurosteroids accumulate in the central nervous system independently of supply by peripheral endocrine glands. Dehydroepiandrosterone (DHA) and pregnenolone (DELTA-5P) were first found in the rat brain. Then, a steroid biosynthetic pathway was demonstrated in oligodendrocytes, mostly by enzyme immunocytochemistry and biochemical studies in primary cultures of glial cells, where the formation, from appropriate radioactive precursors, of DELTA-5P, DELTA-5-pregn-3-beta,20-alpha-diol (20-alpha-DH-DELTA-5P), progesterone (P), 5-alpha-pregnane-3,20-dione (5-alpha-DHP) and 3-alpha-hydroxy-5-alpha-pregnane-20-one (3-alpha, 5-alpha-THP), as well as estrogen-induced nuclear progesterone receptor (PR) was observed. Several biological effects of neurosteroids have been observed, such as electrical stimulation of neurones, involvement in behavorial activities, modulation of GABA(A)-receptor (GABA(A)-R) function (potentiated by 3-alpha,5-alpha-THP and its 21-hydroxyderivative, antagonized by DELTA-5P- and DHA-sulfates) and growth/differentiation of glial cells in vitro. Preliminary findings suggest that the neurosteroid concept applies to all mammalian species, including man. Further investigations should assess the pathophysiological significance of the synthesis of neurosteroids and decipher their mechanisms of action via nuclear and membrane receptors.