Local synthesis and dual action of progesterone in the nervous system: neuroprotection and myelination

SCHUMACHER; GENOUUN; ROBERT; CARILLI; GAGO; GHOUMARI, A; GONZÁLEZ DENISELLE MC; GONZALEZ S; IBANEZ C; LABOMBARDA F; COIRINI H; BAULIEU, E; DE NICOLA A

GROWTH HORMONE & IGF RESEARCH : OFFICIAL JOURNAL OF THE GROWTH HORMONE RESEARCH SOCIETY AND THE INTERNATIONAL IGF RESEARCH SOCIETY.

CHURCHILL LIVINGSTONE

Año: 2004 vol. 14 p. 18 - 33

1096-6374

Progesterone (PROG) is synthesized in the brain, spinal cord and peripheral nerves. Its direct precursor pregnenolone is eitherderived from the circulation or from local de novo synthesis as cytochrome P450scc, which converts cholesterol to pregnenolone, isexpressed in the nervous system. Pregnenolone is converted to PROG by 3b-hydroxysteroid dehydrogenase (3b-HSD). In situhybridization studies have shown that this enzyme is expressed throughout the rat brain, spinal cord and dorsal root ganglia (DRG)mainly by neurons. Macroglial cells, including astrocytes, oligodendroglial cells and Schwann cells, also have the capacity tosynthesize PROG, but expression and activity of 3b-HSD in these cells are regulated by cellular interactions. Thus, Schwann cellsconvert pregnenolone to PROG in response to a neuronal signal.There is now strong evidence that P450scc and 3b-HSD are expressed in the human nervous system, where PROG synthesis alsotakes place. Although there are only a few studies addressing the biological significance of PROG synthesis in the brain, the autocrine/paracrine actions of locally synthesized PROG are likely to play an important role in the viability of neurons and in theformation of myelin sheaths. The neuroprotective effects of PROG have recently been documented in a murine model of spinal cordmotoneuron degeneration, the Wobbler mouse. The treatment of symptomatic Wobbler mice with PROG for 15 days attenuated theneuropathological changes in spinal motoneurons and had beneficial effects on muscle strength and the survival rate of the animals.PROG may exert its neuroprotective effects by regulating expression of specific genes in neurons and glial cells, which may becomehormone-sensitive after injury.The promyelinating effects of PROG were first documented in the mouse sciatic nerve and in co-cultures of sensory neurons andSchwann cells. PROG also promotes myelination in the brain, as shown in vitro in explant cultures of cerebellar slices and in vivo inthe cerebellar peduncle of aged rats after toxin-induced demyelination. Local synthesis of PROG in the brain and the neuroprotectiveand promyelinating effects of this neurosteroid offer interesting therapeutic possibilities for the prevention and treatment ofneurodegenerative diseases, for accelerating regenerative processes and for preserving cognitive functions during aging.