RESUMEN
Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) ß ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of endogenous myelination. The direct cellular mechanisms underlying the effects of this ERß ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ERß is the target molecule of DPN because DPN treatment fails to decrease EAE clinical symptoms in global ERß-null mice. Here we investigated the potential role of ERß expression in cells of oligodendrocyte (OL) lineage in ERß ligand-mediated neuroprotection. To this end, we selectively deleted ERß in OLs using the well-characterized Cre-loxP system for conditional gene knockout (CKO) in mice. The effects of this ERß CKO on ERß ligand-mediated neuroprotective effects in chronic EAE mice were investigated. ERß CKO in OLs prevented DPN-induced decrease in EAE clinical disease. DPN treatment during EAE did not attenuate demyelination, only partially improved axon conduction, and did not activate the phosphatidylinositol 3-kinase/serine-threonine-specific protein kinase/mammalian target of rapamycin signaling pathway in ERß CKO mice. However, DPN treatment significantly increased brain-derived neurotrophic factor levels in ERß CKO mice. These findings demonstrate that signaling through ERß in OLs is essential for the beneficial myelination effects of the ERß ligand DPN in chronic EAE mice. Further, these findings have important implications for neuroprotective therapies that directly target OL survival and myelination.