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

WIES MANCINI V.B.1, DI PIETRO A.PASQUINI JM, OLMOS S, CORREALE J.D., PASQUINI L.A.

Congreso; XXXIV Annual Meeting of the Argentine Society for Research in Neuroscience (SAN); 2019

SAN

Cuprizone(CPZ)-induced demyelination is widely used as a multiplesclerosis (MS) model to study de/remyelination processes.Microglia (MG) participate in demyelination and neurodegeneration processes andare physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R)signaling. Therefore, we aimed to evaluate the effects of CSF-1R inhibitorBLZ945 on demyelination and neuroregeneration in mice submitted to chronic CPZ demyelination. Mice were fed either control or CPZ (0.2% w/w) chow for12 weeks and orally gavaged vehicle or BLZ (200 mg/kg/day) from the 2nd week ofCPZ treatment (C, BLZ, CPZ and CPZ+BLZ). BLZ treatment induced a reduction inthe number of MG in all structures evaluated and attenuated demyelination in corpuscallosum (CC), striatum (ST), fimbria (F), external splenium CC (ESCC) and cerebellum(CE). Positive amino-cupric-silver (ACS) staining was prominent in axonstraversing the ST and fibers throughout the CC, ESCC, F and CE in CPZ andCPZ+BLZ, and even more prominent in ST and CC in CPZ+BLZ. Axonal degenerationwas accompanied by terminal axonal ovoids characteristic of inflammatorydemyelination. ACS staining was hardly observed in axonal terminal puncta atsynaptic sites or neuron bodies. These results indicate that neurodegenerationdoes not exclusively result from demyelination and that MG depletion couldprevent demyelination but also exacerbate axonal degeneration. These data couldbe transferred to the treatment of progressive MS.