Neurosteroidogenesis is recovered by Progesterone treatment of experimental autoimmune encephalomyelitis and during spontaneous remyelination in the cuprizone model of demyelination

LAURA INÉS GARAY; MARÍA LUZ LEICAJ; MARÍA CLAUDIA GONZALEZ DENISELLE; LAURA PASQUINI; JUANA MARÍA PASQUINI; ALEJANDRO FEDERICO DE NICOLA

Edimburgo

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

Previous studies of murine experimental autoimmune encephalomyelitis (EAE) have shown that progesterone pre-treatment decreases inflammatory cell infiltration and proinflammatory factors, increases myelination and attenuates clinical grade of the affected mice (Garay 2007, 2012). To elucidate potential mechanisms for these progesterone effects, we analyzed the mRNA levels of neurosteroidogenic enzymes in the spinal cord of EAE mice and in the hippocampus of cuprizone-fed mice. We found in steroid-untreated EAE and cuprizone treated mice decreased mRNA expression of the steroidogenic acute regulatory protein (STAR), P450scc (cholesterol side-chain cleavage), 5 -reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD). Aromatase was decreased only in the EAE model, whereas mRNA levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) showed a large intergroup variation in both models. Altered expression of neurosteroidogenic enzyme mRNA was accompanied by decreased myelin basic protein (MBP) mRNA expression. We also found increased mRNA expression of 18 Kd translocator protein (TSPO), which likely originated on the reactive microgliosis revealed by increased CD11b and TNFα mRNA in the spinal cord as well as in hippocampus of demyelinated mice. Pretreatment with progesterone (100 mg pellet) a week before EAE induction increased STAR, VDAC, P450scc, 5α-reductase, 3α-HSD and aromatase mRNAs and did not modify 3β-HSD. TSPO mRNA was decreased, in line with inhibition of microgliosis. Fifteen days after cuprizone removal, spontaneous hippocampal remyelination was demonstrated by the increased MBP expression and attenuation of CD11b and TNFα related-microgliosis. In this cuprizone-free period, steroidogenic enzymes expression recovered the levels of control mice. Our results demonstrated that demyelination and neuroinflammation is associated with reduced neurosteroidogenesis. We hypothesized that restoration of protective steroid products may potentiate progesterone´s beneficial effects in murine EAE and may also have a role in recovery from cuprizone-induced demyelination.