NEUROSTEROIDOGENESIS AND PROGESTERONE ANTI-INFLAMMATORY/ NEUROPROTECTIVE EFFECTS

GUENNOUN R; FLORENCIA LABOMBARDA; GONZALEZ DENISELLE, MARÍA CLAUDIA; REGINE SITRUK-WARE; ALEJANDRO F. DE NICOLA; MICHAEL SCHUMACHER; MARIA MEYER

Turin

Conferencia; 9th International Meeting on Steroids and Nervous System; 2017

NEUROSTEROIDOGENESISAND PROGESTERONE ANTI-INFLAMMATORY/ NEUROPROTECTIVE EFFECTS.De Nicola A.F. *,**, Garay L. *, **, Meyer M. **, Sitruk-Ware R. #,Guennoun R. o, Schumacher M. o,Gonzalez Deniselle M.C. **, ***. * Dept. of Human Biochemistry, Faculty of Medicine,University of Buenos Aires, 1425 Buenos Aires, Argentina;  ** Instituto de Biologia y MedicinaExperimental-CONICET, 1428 Buenos Aires, Argentina;  oU1195 Inserm and Université Paris-Sud, 94276 Le Kremlin-Bicêtre, France. # The Population Council, New York,NY 10021, USA.; *** Dept. of Physiology and Biophysics, Faculty of Medicine,University of Buenos Aires, 1425 Buenos Aires, Argentina. Multiplesclerosis (MS) is a neurological autoimmune/neurodegenerative disorder [8] thataffects about 2.5 million people worldwide, according to WHO reports. A rolefor steroid hormones in MS is suggested because relapses decline during thelast trimester of pregnancy, when estrogens and progesterone levels are high,and resume when steroids decay after delivery [2]. A commonly used model of MSis experimental autoimmune encephalomyelitis (EAE), induced in rodents byimmunization with myelin peptides. We and others have shown that progesteronetreatment decreases inflammatory cell infiltration and proinflammatory markers(TNFalpha, TNFR1, TLR4), increases myelination and attenuates clinical grade ofEAE rodents [3-6]. The anti-inflammatory effects of progesterone in EAE arereminiscent of the changes from a TH1 to a TH2 response exerted by this steroidin pregnancy. In EAE, some of the progesterone effects may involve theclassical progesterone receptor (PR), because the high affinity PR agonistNestorone® decreases clinical grade, improves motor behaviour and decreasesreactive microglia of EAE mice [6]. `Since neurosteroids have been implicatedas protective factors for MS and EAE [3,7] we analyzed the mRNA expression ofneurosteroidogenic enzymes in the spinal cord, a major target of EAE.. Becausemitochondria are the initial site of neurosteroid synthesis, we also analyzedmitochondrial morphology and dynamics (fusion and fission proteins). EAE wasinduced in female C57Bl6 mice using MOG40-54 and killed on day 16 afterinduction. Progesterone was given by pellet implantation 1 week before EAEinduction. Using qPCR, we found in steroid-untreated EAE mice decreased mRNAsfor the steroidogenic acute regulatory protein (Star), voltage-dependent anionchannel (VDAC), P450scc (cholesterol side-chain cleavage), 5a-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSD) and aromatase, whereas levelsof 3b-hydroxysteroid dehydrogenase (3b-HSD) showed a large intra-group variance. Wealso found increased mRNA expression of 18 Kd translocator protein (TSPO),which likely resulted from the reactive microgliosis in this model. EAE micealso showed pathological mitochondrial morphology in axons and neuronal body,and reduced expression of fission and fusion protein mRNAs. Most importantly,pretreatment with progesterone before EAE induction increased Star,VDAC,P450scc, 5a-reductase type I, 3α-HSD and aromatase mRNAs and did notmodify 3b-HSD. TSPO mRNA was decreased,consequent with the inhibition of microgliosis. Mitochondrial morphology wasimproved and fission/fusion protein mRNAs were enhanced by progesteronetreatment. Furthermore, progesterone protective effects on mitochondrial andendoplasmic reticulum may allow the recovery of neurosteroidogenesis. Inaddition to progestins and estrogens, the enzymes 3b-HSD, 3a-HSD and 5a-reductase are also responsible for theformation of androgens. Since androgen levels are modified in MS patients andEAE models [1,3], it is likely that together with progestins and estrogens,neuroandrogens may play a protective role for EAE and MS outcome. .Our presentdata suggest that enhanced synthesis of neurosteroids in the spinal cord mayreinforce the neuroprotective and anti-inflammatory effects of exogenousprogesterone given to EAE mice.ReferenceList[1] CarusoD., G. D´Intino, S. Giatti, O. Maschi, M. Pesaresi, D. Calabrese, L.M.Garcia-Segura, L. Calza , R.C. Melcangi., Sex-dimorphic changes in neuroactivesteroid levels after chronic experimental autoimmune encephalomyelitis, JNeurochem. 114 (2010) 921-932.[2]Confavreux C., M. Hutchinson, M. M. Hours, P. Cortinovis-Tourniaire, T. Moreau,Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in MultipleSclerosis Group, N Engl J Med. 339 (1998) 285-291[3] Giatti,S., D. Caruso, M. Boraso, F. Abbiati, E. Ballarini, D. Calabrese, M. Pesaresi,R. Rigolio, M. Santos-Galindo, B. Viviani, G. Cavaletti, L.M. Garcia-Segura,R.C. Melcangi., Neuroprotective effects of progesterone in chronic experimentalautoimmune encephalomyelitis, J Neuroendocrinol. 24 (2012) 851-861.[4] GarayL., M. C. Gonzalez Deniselle, A. Lima, P. Roig, A. F. De Nicola, Effects ofprogesterone in the spinal cord of a mouse model of multiple sclerosis, JSteroid Biochem Mol Biol. 107 (2007) 228-237.[5] GarayL., M. C. Gonzalez Deniselle, M. E. Brocca, A. Lima, P. Roig, A. F. De Nicola,Progesterone down-regulates spinal cord inflammatory mediators and increasesmyelination in experimental autoimmune encephalomyelitis, Neuroscience. 226(2012) 40-50. [6] GarayL., M. C. Gonzalez Deniselle, R. Sitruk-Ware, R. Guennoun, M. Schumacher, A. F.De Nicola, Efficacy of the selective progesterone receptor agonist Nestoronefor chronic experimental autoimmune encephalomyelitis, J Neuroimmunol. 276(2014) 89-97. [7]Noorbakhsh F. , K. K. Ellestad, F. Maingat, K. G. Warren, M. H. Han, L.Steinman, G.B. Baker, C. Power., Impaired neurosteroid synthesis in multiplesclerosis, Brain. 134 (2011) 2703-2721.[8] TrappB.D., K. A. Nave, Multiple sclerosis: an immune or neurodegenerative disorder?,Annu Rev Neurosci. 31 (2008) 247-269.