Modulators of oligodendrocyte progenitors maturation: New candidates for treatment of multiple sclerosis.

摘要

Multiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the central nervous system (CNS) characterized by lesions at different locations in the myelinated areas of the CNS. Experimental autoimmune encephalomyelitis (EAE) is the most studied model of MS, and shares clinical, immunological, and histological features with MS.;The role of Peroxisome Proliferator-Activated Receptor delta (PPARdelta) and noradrenaline (NA) in oligodendrocyte precursor cell (OPC) maturation has been investigated. In vitro studies show that in primary OPCs, the selective PPARdelta agonist, GW0742, and the catecholamine NA increase OPC maturation, inducing myelin genes expression. Moreover, modulation of bone morphogenetic proteins (BMP), and BMP antagonists' expression contribute to the feed-forward effect GW0742 and NA exert in OPCs. However, PPARdelta and NA adopt different mechanisms in inducing OPC maturation.;The MOG-induced EAE mouse model of MS was used for in vivo studies to investigate on the beneficial effects GW0742, L-DOPS (a precursor of NA), and the NA re-uptake inhibitor (NARI) atomoxetine have on EAE.;Studies on PPARdelta-null and WT EAE mice show that PPARdelta is responsible for the beneficial effect of GW0742 on EAE clinical signs, and that PPARdelta is not involved in the patho-physiological mechanisms of EAE. In EAE mice, damage at the locus coeruleus contributes to worsening of the disease. Treatment of EAE with L-DOPS, and the NARI atomoxetine attenuates and/or reduce clinical signs of the disease. Overall, these findings show that in vitro PPARdelta and NA promote OPC maturation, and in vivo they contribute to the amelioration of EAE. GW0742, L-DOPS, and atomoxetine may then represent an alternative strategy for treatment of EAE and MS by inducing attenuation and recovery.