Changes in neuroesteroidogenesis in demyelination and remyelination

ALEJANDRO DE NICOLA; ANALIA LIMA; LAURA GARAY; JUANA MARÍA PASQUINI; LAURA PASQUINI; MARIA LUZ LEICAJ

Congreso; THE ROLE OF GLIAL CELLS IN HEALTH AND DISEASE OF THE NERVOUS SYSTEM:CLINICAL AND BASIC SCIENCE WALKING TOGETHER; 2017

 Studies of Multiple Sclerosis and murine experimentalautoimmune encephalomyelitis (EAE) have shown altered neurosteroidogenesis. Wepreviously demonstrated that Progesterone pre-treatment decreasesdemyelination, neuroinflammation, improves clinical grade and re-establishes steroidogenicenzymes levels in the spinal cord of EAE mice (Garay 2007,2012,2017). Here, we asseshippocampal steroidogenic pathway in a cuprizone model of demyelination. We alsoanalysed demyelination and neuroinflammation parameters in the hippocampus of control(CTRL), demyelinated (CPZ D), and remyelinated (CPZ R) mice. We found in CPZ D mice hippocampus decreased mRNAexpression of the steroidogenic acute regulatory protein (STAR), P450scc(cholesterol side-chain cleavage), 5 a-reductase (CPZD vs. CTRL;p<0.05) whereas mRNA levels of 3b-hydroxysteroid dehydrogenase (3b-HSD) showed a large intergroup variation. Altered expression ofneurosteroidogenic enzyme mRNA was accompanied by decreased myelin basicprotein (MBP) mRNA and protein levels (CPZ D vs CTRL;p<0.05). We also foundincreased mRNA expression of 18 Kd translocator protein (TSPO), which likelyoriginated on the reactive microgliosis revealed by increased number of iba1+cells and CD11b and TNFα mRNAs (CPZ vs CTRL,p<0.001). Fifteen days aftercuprizone removal, spontaneous hippocampal remyelination was demonstrated bythe increased MBP expression and attenuation of CD11b, TNFαrelated-microgliosis and TSPO mRNA. In this cuprizone-free period,steroidogenic enzymes expression recovered the levels of control mice (CPZ R vsCTRL;ns). Our results demonstrated that demyelination and neuroinflammation isassociated with reduced neurosteroidogenesis. We hypothesized that restorationof protective steroid products, eg.Progesterone, may have a role in recoveryfrom cuprizone-induced demyelination.