Impact of microglial depletion through colony-stimulating receptor 1 inhibition on demyelination and neurodegeneration in a chronic cuprizone-induced demyelination model

VICTORIA S.B. WIES MANCINI; ANABELLA A. DI PIETRO; DE OLMOS S; PASQUINI, JUANA M.

Villa carlos Paz

Congreso; SAN 2019; 2019

Cuprizone (CPZ)-induced demyelination is widely used as amultiple sclerosis (MS) model to study de/remyelination processes. Microglia (MG) participate in demyelination and neurodegeneration processes and are physiologically dependenton colony-stimulating factor 1 receptor (CSF-1R) signaling.Therefore, we aimed to evaluate the effects of CSF-1R inhibitor BLZ945 on demyelination and neuroregeneration inmice submitted to chronic CPZ demyelination. Mice werefed either control or CPZ (0.2% w/w) chow for 12 weeksand orally gavaged vehicle or BLZ (200 mg/kg/day) from thesecond week of CPZ treatment (C, BLZ, CPZ andCPZþBLZ). BLZ treatment induced a reduction in thenumber of MG in all structures evaluated and attenuateddemyelination in corpus callosum (CC), striatum (ST), fimbria (F), external splenium CC (ESCC) and cerebellum (CE).Positive amino-cupric-silver (ACS) staining was prominent inaxons traversing the ST and fibers throughout the CC,ESCC, F and CE in CPZ and CPZþBLZ, and even moreprominent in ST and CC in CPZþBLZ. Axonal degenerationwas accompanied by terminal axonal ovoids characteristic ofinflammatory demyelination. ACS staining was hardlyobserved in axonal terminal puncta at synaptic sites orneuron bodies. These results indicate that neurodegeneration does not exclusively result from demyelination and thatMG depletion could prevent demyelination but also exacerbate axonal degeneration. These data could be transferredto the treatment of progressive MS.