NEUROSTEROIDOGENESIS IS RECOVERED DURING SPONTANEOUS REMYELINATION IN THE CUPRIZONE MODEL OF DEMYELINATION

PASQUINI JUANA; LIMA, A; DE NICOLA A. F.; GONZALEZ DENISELLE, MC; GARAY L; PASQUINI LAURA; LEICAJ LUZ

Congreso; Reunión Anual Conjunta de las Sociedades de Biociencias; 2017

Studies of Multiple Sclerosis and murine experimental autoimmuneencephalomyelitis (EAE) have shown altered neurosteroidogenesis.We previously demonstrated that Progesterone pre-treatment decreasesdemyelination, neuroinflammation, improves clinical gradeand re-establishes steroidogenic enzymes levels in the spinal cordof EAE mice (Garay 2007,2012,2017). Here, we asses hippocampalsteroidogenic pathway in a cuprizone model of demyelination. Wealso analysed demyelination and neuroinflammation parametersin the hippocampus of control (CTRL), demyelinated (CPZ D), andremyelinated (CPZ R) mice. We found in CPZ D mice hippocampusdecreased mRNA expression of the steroidogenic acute regulatoryprotein (STAR), P450scc (cholesterol side-chain cleavage),5 a-reductase (CPZ D vs. CTRL;p<0.05) whereas mRNA levels of3b-hydroxysteroid dehydrogenase (3b-HSD) showed a large intergroupvariation. Altered expression of neurosteroidogenic enzymemRNA was accompanied by decreased myelin basic protein (MBP)mRNA and protein levels (CPZ D vs CTRL;p<0.05). We also foundincreased mRNA expression of 18 Kd translocator protein (TSPO),which likely originated on the reactive microgliosis revealed byincreased number of iba1+ cells and CD11b and TNFα mRNAs(CPZ vs CTRL,p<0.001). Fifteen days after cuprizone removal,spontaneous hippocampal remyelination was demonstrated by theincreased MBP expression and attenuation of CD11b, TNFα related-microgliosis and TSPO mRNA. In this cuprizone-free period,steroidogenic enzymes expression recovered the levels of controlmice (CPZ R vs CTRL;ns). Our results demonstrated that demyelinationand neuroinflammation is associated with reduced neurosteroidogenesis.We hypothesized that restoration of protective steroidproducts, eg.Progesterone, may have a role in recovery from cuprizone-induced demyelination.