Progesterone treatment modulates mRNA OF neurosteroidogenic enzymes in a murine model of multiple sclerosis.
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 MOG40-54and 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 18Kd 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.
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina; Dept. of Human Biochemistry(,) Faculty of Medicine, University of Buenos Aires, Argentina.
Laura
L
Garay
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina.
Paula
P
Gonzalez Giqueaux
U1195 Inserm and University Paris-Sud and University Paris-Saclay, Kremlin-Bicêtre, France.
Rachida
R
Guennoun
U1195 Inserm and University Paris-Sud and University Paris-Saclay, Kremlin-Bicêtre, France.
Michael
M
Schumacher
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina; Dept. of Human Physiology, Faculty of Medicine, University of Buenos Aires, Argentina.
Maria Claudia
MC
Gonzalez Deniselle
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina; Dept. of Human Biochemistry(,) Faculty of Medicine, University of Buenos Aires, Argentina. Electronic address: alejandrodenicola@gmail.com.
Alejandro F
AF
De Nicola
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
D018377:Neurotransmitter Agents; D010750:Phosphoproteins; D012333:RNA, Messenger; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D042944:Cholestenone 5 alpha-Reductase
Experimental autoimmune encephalomyelitis; Neuroprotection; Neurosteroidogenesis; Progesterone