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

VICTORIA SOFÍA BERENICE WIES MANCINI1; ANABELLA AYELEN DI PIETRO; SOLEDAD DE OLMOS; JUANA MARÍA PASQUINI1; JORGE DANIEL CORREALE2; LAURA ANDREA PASQUINI1.

Villa Carlos Paz, Córdoba

Congreso; XXXIV Reunión Anual SAN 2019; 2019

Cuprizone (CPZ)-induced demyelination is widely used as a multiple sclerosis (MS) model to study de/remyelination processes. Microglia (MG) participate in demyelination and neurodegeneration processes and are physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R) signaling. Therefore, we aimed to evaluate the effects of CSF-1R inhibitor BLZ945 on demyelination and neuroregeneration in mice submitted to chronic CPZ demyelination. Mice were fed either control or CPZ (0.2% w/w) chow for 12 weeks and orally gavaged vehicle or BLZ (200 mg/kg/day) from the 2nd week of CPZ treatment (C, BLZ, CPZ and CPZ+BLZ). BLZ treatment induced a reduction in the number of MG in all structures evaluated and attenuated demyelination in corpus callosum (CC), striatum (ST), fimbria (F), external splenium CC (ESCC) and cerebellum (CE). Positive amino-cupric-silver (ACS) staining was prominent in axons traversing the ST and fibers throughout the CC, ESCC, F and CE in CPZ and CPZ+BLZ, and even more prominent in ST and CC in CPZ+BLZ. Axonal degeneration was accompanied by terminal axonal ovoids characteristic of inflammatory demyelination. ACS staining was hardly observed in axonal terminal puncta at synaptic sites or neuron bodies. These results indicate that neurodegeneration does not exclusively result from demyelination and that MG depletion could prevent demyelination but also exacerbate axonal degeneration. These data could be transferred to the treatment of progressive MS.