Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5513153 | The Journal of Steroid Biochemistry and Molecular Biology | 2017 | 9 Pages |
Abstract
Previous studies of experimental autoimmune encephalomyelitis (EAE) have shown that progesterone decreases inflammatory cell infiltration and proinflammatory factors, increases myelination and attenuates clinical grade of EAE mice. To elucidate potential mediators of these effects, we analyzed the mRNA expression of neurosteroidogenic enzymes in the spinal cord, in view of the protective role of steroids in EAE. We also analyzed mitochondrial morphology and dynamics (fusion and fission proteins), considering the role of mitochondria in neurosteroidogenesis. EAE was induced in C57Bl6 mice using MOG40-54 and killed on day 16 after induction. Using qPCR, we found in steroid-untreated EAE mice decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), P450scc (cholesterol side-chain cleavage), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSD) and aromatase, whereas levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) showed a large intra-group variance. We also found increased mRNA expression of 18 Kd translocator protein (TSPO), which likely resulted from the reactive microgliosis in this model. EAE mice also showed pathological mitochondrial morphology and reduced expression of fission and fusion protein mRNAs. Most importantly, pretreatment with progesterone a week before EAE induction increased Star,VDAC, P450scc, 5α-reductase type I, 3α-HSD and aromatase mRNAs and did not modify 3β-HSD. TSPO mRNA was decreased, consequent with the inhibition of microgliosis. Mitochondrial morphology was improved and fission/fusion protein mRNAs were enhanced by progesterone treatment. Furthermore, progesterone protective effects on mitochondrial and endoplasmic reticulum may allow the recovery of neurosteroidogenesis. In this way, endogenously synthesized neurosteroids may reinforce the beneficial effects of exogenous progesterone previously shown in MS mice.
Keywords
cluster of differentiation molecule 11bNMDAN-methyl-d-aspartateoligodendrocyte transcription factor 1TSPOFis1THPCD11BTLR4VDACPLPCC1TNFaPROGMFN2DHPNKX2.2NeurosteroidogenesisMBPNK2 Homeobox 2CFAMOG3β-HSD3α-HSDOlig1EAETNFR1Proteolipid proteinexperimental autoimmune encephalomyelitisgamma-aminobutyric acidTetrahydroprogesteronetumor necrosis factor alphaprogesterone receptor membrane component 1dihydroprogesteroneStarlipopolysaccharideNeuroprotectionMultiple sclerosismitofusin 2Steroidogenic acute regulatory proteinMyelin basic proteinProgesteroneComplete Freund adjuvantvoltage-dependent anion channelGABAToll-like receptor 4Progesterone receptor
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Authors
Laura Garay, Paula Gonzalez Giqueaux, Rachida Guennoun, Michael Schumacher, Maria Claudia Gonzalez Deniselle, Alejandro F. De Nicola,