Reduced microglial activation through the inhibition of colony-stimulating factor 1 receptor (CSF1R) to promote remyelination and neuroprotection

VICTORIA SOFÍA BERENICE WIES MANCINI1; JUANA MARÍA PASQUINI1; JORGE DANIEL CORREALE2; LAURA ANDREA PASQUINI1.

Capital Federal, Buenos Aires, Argentina

Workshop; The role of glial cells in health and disease of the Nervous System: clinical and basic science walking together; 2017

Multiple Sclerosis (MS) is one of the most common causes of progressive disabilityaffecting young people, yet therapeutic options available for progressive MS aredisappointing and remain a challenge. Demyelination and neurodegeneration involve theactivation of microglial cells, which are in turn physiologically dependent on colonystimulating factor 1 receptor (CSF-1R) signaling. In the present work, we used microglialmodulation through oral administration of brain-penetrant CSF-1R inhibitor BLZ945 andacute and chronic cuprizone (CPZ)-induced demyelination to evaluate preventive andtherapeutic effects on de/remyelination and neurodegeneration. Our results show thatBLZ945 induced a significant reduction in the number of microglia and their shift toward anM2 and phagocytic phenotype, without alterations in peripheral macrophages. PreventiveBLZ945 treatment attenuated demyelination in both CPZ models, while therapeutictreatment promoted remyelination and neuroprotection in the chronic model. These resultscould be potentially transferred to the treatment of progressive forms of MS.