PROGESTINS AS ANTI-INFLAMMATORY FACTORS IN NEUROLOGICAL DISORDERS.

GARAY L; MEYER M; GONZALEZ DENISELLE MC; DE NICOLA A. F.

Congreso; 2nd Congress of the Federation of Latin-American and Caribbean Societies for Neuroscience (FALAN); 2016

Progesterone exerts neuroprotective effects in several CNS diseases. These properties are additional to their reproductive functions. In murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), progesterone treatment decreased cell infiltration, changed the microglia phenotype and reduced the expression of the proinflammatory factors and enzymes TNFalpha, TLR4, COX2 and iNOS. Concomitantly, there was increased expression of myelin central proteins and oligodendrocyte progenitors. To elucidate mediators of these effects, we analyzed the expression of neurosteroidogenic enzymes, because locally synthesized neurosteroids play an autocrine/paracrine neuroprotective role. We found that progesterone-treatment of EAE mice restored the mRNA levels for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), P450scc (cholesterol side-chain cleavage), 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) and aromatase, whereas levels of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) showed a large intra-group variance. We also found that the 18 Kd translocator protein (TSPO), a marker of reactive microgliosis was decreased, consequent with the inhibition of microglia reactivity. EAE mice showed pathological mitochondrial morphology and reduced expression of fission and fusion proteins, parameters restored by progesterone treatment We hypothesized that progesterone protective effects on mitochondrial and endoplasmic reticulum may allow the recovery of neurosteroidodogenesis. In this way, endogenously synthesized neurosteroids may reinforce the beneficial effects of exogenous progesterone shown in MS mice.