CONICET | Buscador de Institutos y Recursos Humanos

Multiplesclerosis (MS) is one of the most common causes of progressive disabilityaffecting young people with very few therapeutic options available for itsprogressive forms. Its pathophysiology involves demyelination andneurodegeneration apparently driven by microglial activation, which isphysiologically dependent on colony-stimulating factor-1 receptor (CSF-1R)signaling. In the present work, we used microglial modulation through oraladministration of brain-penetrant CSF-1R inhibitor BLZ945 in acute and chroniccuprizone (CPZ)-induced demyelination to evaluate preventive and therapeuticeffects on de/remyelination and neurodegeneration. Our results show that BLZ945induced a significant reduction in the number of microglia. Preventive BLZ945treatment attenuated demyelination in the acute CPZ model, mainly in cortex andexternal capsule. In contrast, BLZ945 treatment in the acute CPZ model failedto protect myelin or foster remyelination in myelin-rich areas, which mayrespond to a loss in microglial phagocytic capacity and the consequentimpairment in oligodendroglial differentiation. Preventive and therapeuticBLZ945 treatment promoted remyelination and neuroprotection in the chronicmodel. These results could be potentially transferred to the treatment of progressiveforms of MS.