Microglial response modulation through the inhibition of colony-stimulating factor 1 receptor (CSF-1R) to promote remyelination and neuroprotection

V. S. B. WIES MANCINI, J. M. PASQUINI, J. D. CORREALE, L. A. PASQUINI

Edimburg, Escocia

Congreso; XIII European Meeting on Glial Cells in Health and Disease.; 2017

Glia

Multiple Sclerosis (MS) is one of the most commoncauses of progressive disability affecting young people in their productivelife stage. Most patients initially present a relapsing-remitting course which,after 10 to 15-year evolution, becomes progressive in up to 50% patients, withclinical symptoms slowly but steadily deteriorating. In about 15% MS patients,disease progression is relentless from disease onset. In recent decades, abetter understanding of relapsing-remitting MS disease mechanisms has led tothe development of several disease-modifying therapies. By contrast,therapeutic options available for progressive disease are disappointing andremain a challenge. In this context, a 0.2% cuprizone (CPZ) diet administeredto adult mice over 5 to 6 weeks induces demyelination in the corpus callosum(acute model), with spontaneous remyelination following CPZ withdrawal. A12-week CPZ diet (chronic model), however, fails to trigger a successfulremyelination process upon CPZ withdrawal, leading to progressive disability. Thesefindings hint at the possible use of the CPZ model to develop therapeuticagents enabling remyelination and preventing neurodegeneration. Differentstudies have highlighted the active participation of microglia in the processesof demyelination and neurodegeneration. The inhibition of CSF1R results in the eliminationof ~99% of microglia brain-wide, showing that microglial cells in the adultbrain are physiologically dependent on CSF1R signaling. BLZ945 is abrain-penetrant CSF1R inhibitor which substantially reduces the number ofmicroglia in normal brains when administered orally. In this context, thepresent work proposes the use of the CPZ model to test the potential of BLZ945as a molecule capable of stimulating remyelination and/or preventingneurodegeneration by the depletion of microglia. By means of immunostaining andelectron microscopy, we found BLZ945 treatment to reduce both demyelination (MBP)and microglial activation (Iba-1 and Griffonia)in the acute CPZ protocol. Moreover, in both control and demyelinated animals,BLZ945 treatment increased astroglial activation (GFAP). In the chronicprotocol, treated animals showed less demyelination, which suggests that BLZ945either protected myelin from degradation and/or fostered remyelination.Positive results from these experiments could be transferred to the treatmentof progressive forms of MS, an urgent and still unmet medical need.