Nestorone effects in other models: EAE, Wobbler

ALEJANDRO F. DE NICOLA

Nueva York

Workshop; THE NESTORONE GLOBAL BRAIN NEURAL NETWORK; 2017

Population Cooucil

An increasing number of reports supports that progesterone providesneuroprotection against CNS diseases. In the experimental autoimmuneencephalomyelitis (EAE) model of multiple sclerosis (MS), progesteronetreatment decreased cell infiltration, changed microglia phenotype and reducedthe proinflammatory mediators TNFalpha, TLR4 and iNOS in the spinal cord.Concomitantly, progesterone increased myelin proteins and oligodendrocyteprogenitors. To elucidate possible mediators of these effects, we analyzed themRNA of neurosteroidogenic enzymes, considering that locally synthesizedsteroids bring neuroprotection by autocrine/paracrine mechanisms. We found thatin EAE mice progesterone treatment restored the mRNA for the steroidogenicacute regulatory protein (Star), voltage-dependent anion channel (VDAC),P450scc (cholesterol side-chain cleavage), 5alpha-reductase,3alpha-hydroxysteroid dehydrogenase and aromatase. We also found that the 18 Kdtranslocator protein (TSPO), a marker of reactive microgliosis was decreased,consequent with the inhibition of microglia reactivity. EAE mice showedpathological mitochondrial morphology and reduced expression of fission andfusion proteins, parameters restored by progesterone. These data indicate thatprogesterone neuroprotection include the recovery of neurosteroidodogenesis. Inthis way, endogenously synthesized neurosteroids may reinforce theanti-inflammatory and promyelinating effects of exogenous progesterone found inMS mice