Progesterone and the oligodendroglial lineage: Stage‐dependent biosynthesis and metabolism

Abstract

Evidence has been accumulated showing that neurosteroids, particularly progesterone (PROG) and its metabolites, may participate in myelination and remyelination in the peripheral nervous system, but very few studies have been undertaken in the central nervous system (CNS). The aim of this work was to investigate the capacities of synthesis and metabolism of PROG at three important stages of the oligodendroglial lineage: oligodendrocyte pre-progenitors (OPP), oligodendrocyte progenitors (OP), and fully differentiated oligodendrocytes (OL). Experiments have been conducted in vitro using highly purified primary cell cultures from rat brain. Cells were incubated with (3)H-pregnenolone ((3)H-PREG), the immediate precursor of PROG, or with (3)H-PROG, and steroids metabolites were then identified by thin layer chromatography and high-performance liquid chromatography (HPLC). mRNA expression of key steroidogenic enzymes was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The results showed that only OPP and OP, but not OL, expressed 3 beta-hydroxysteroid dehydrogenase/Delta 5-Delta 4 isomerase mRNA and were able to synthesize PROG from PREG. In the three cell types studied, PROG was metabolized by the type 1 isoform of 5 alpha-reductase into 5 alpha-dihydroprogesterone (5 alpha-DHPROG). This enzyme exhibited a 5-fold higher activity in OL than in OPP and OP. 5 alpha-DHPROG was further transformed either into 3 alpha,5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THPROG), known as a positive allosteric modulator of the GABA(A) receptor, or into the 3 beta-isomer. The 3 alpha,5 alpha-THPROG synthesis was 10 times higher in OPP than in the other cell studied, while the 3 beta,5 alpha-THPROG production did not change with cell differentiation. PROG synthesis and metabolism and the dramatic changes in neurosteroidogenesis observed during the oligodendroglial differentiation may contribute to oligodendrocyte development or the myelination process.

Progesterone Reduces Secondary Damage, Preserves White Matter, and Improves Locomotor Outcome after Spinal Cord Contusion

“…[9][10][11][12][63][64][65][66][67] We have demonstrated in previous works that chronic PROG administration increases the expression of transcription factors that define oligodendrocyte linage, such as Olig2 and Nkx2.2 after spinal cord transection. 21,29 In the present work, we report that PROG treatment reduced the loss of oligodendrocyte numbers and MBP immunoreactivity produced by SCI.…”

The Neurosteroid Allopregnanolone Promotes Proliferation of Rodent and Human Neural Progenitor Cells and Regulates Cell-Cycle Gene and Protein Expression

“…Remarkably, the enzymes 5␣-reductase and 3␣-hydroxysteroid dehydrogenase, required to convert progesterone to its 3␣ metabolites, are present and functional in pluripotential progenitors (Lauber and Lichtensteiger, 1996;Melcangi et al, 1996). In the peripheral nervous system and CNS, both AP␣ and progesterone can promote oligodendrocyte proliferation and myelination (Gago et al, 2001Schumacher et al, 2004).…”

Neurosteroid regulation of central nervous system development

“…Oligodendrocytes and their precursors differentially express enzymes needed for progesterone and other neurosteroid production, suggesting that these compounds may be involved in oligodendrocyte progenitor proliferation and differentiation during development (Gago et al, 2001;Gago et al, 2004;Ghoumari et al, 2005). Oligodendrocyte pre-progenitors, precursors, and fully differentiated oligodendrocytes differentially express 3ßHSD, 5α reductase and 3α hydroxysteroid dehydrogenase (3αHSD).…”