NEUROESTEROIDOGENESIS IS RECOVERED BY PROGESTERONE TREATMENT OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS AND DURING SPONTANEOUS REMYELINATION IN THE CUPRIZONE MODEL OF DEMYELINATION

ALEJANDRO DE NICOLA; JUANA MARÍA PASQUINI; LAURA PASQUINI; GONZALEZ DENISELLE, MARIA CLAUDIA; MARIA LUZ LEICAJ; GARAY LAURA INES

Edimburgo

Congreso; XIII European Meeting on Glial Cells in Health and Disease; 2017

Previous studies of murine experimental autoimmune encephalomyelitis (EAE) haveshown that progesterone pre-treatment decreases inflammatory cell infiltrationand proinflammatory factors, increases myelination and attenuates clinicalgrade of the affected mice (Garay 2007, 2012). To elucidate potentialmechanisms for these progesterone effects, we analyzed the mRNA levels ofneurosteroidogenic enzymes in the spinal cord of EAE mice and in the hippocampusof cuprizone-fed mice. We found in steroid-untreated EAE and cuprizone treatedmice decreased mRNA expression of the steroidogenic acute regulatory protein(STAR), P450scc (cholesterol side-chain cleavage), 5 a-reductase and 3α-hydroxysteroiddehydrogenase (3α-HSD). Aromatase was decreased only in the EAE model, whereasmRNA levels of 3b-hydroxysteroid dehydrogenase (3b-HSD) showed a large intergroup variation in both models. Altered expressionof neurosteroidogenic enzyme mRNA was accompanied by decreased myelin basicprotein (MBP) mRNA expression. We also found increased mRNA expression of 18 Kdtranslocator protein (TSPO), which likely originated on the reactivemicrogliosis revealed by increased CD11b and TNFα mRNA in the spinal cord aswell as in hippocampus of demyelinated mice. Pretreatment with progesterone (100mg pellet) a week before EAE induction increased STAR, VDAC, P450scc, 5a-reductase, 3α-HSD and aromatase mRNAs and did not modify 3b-HSD. TSPO mRNA was decreased, in line with inhibition of microgliosis. Fifteendays after cuprizone removal, spontaneous hippocampal remyelination wasdemonstrated by the increased MBP expression and attenuation of CD11b and TNFαrelated-microgliosis. In this cuprizone-free period, steroidogenic enzymesexpression recovered the levels of control mice. Our results demonstrated that demyelinationand neuroinflammation is associated with reduced neurosteroidogenesis. We hypothesizedthat restoration of protective steroid products may potentiate progesterone´sbeneficial effects in murine EAE and may also have a role in recovery fromcuprizone-induced demyelination.