Inhibition of colony-stimulating factor 1 receptor through BLZ945: impact on remyelination, neurodegeneration and behavior

WIES MANCINI VSB; SILVA PR; PASQUINI JM; CORREALE JD; MARDER M; IGAZ LM; PASQUINI LA

Cordoba

Congreso; XXXIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2018

Sociedad Argentina de Investigación en Neurociencias (SAN)

Cuprizone (CPZ)-induceddemyelination is frequently used to study the de/remyelination processes as a multiple sclerosis(MS) model. Chronic CPZ induces oligodendrocyte loss, neuronal death,astrocytosis and microgliosis. Microglia (MG) participate in demyelination andneurodegeneration processes and are physiologically dependent oncolony-stimulating factor 1 receptor (CSF-1R) signaling. The aim of this studyis to evaluate the effects of BLZ945 ‒a CSF-1R inhibitor which significantlyreduces the number of MG‒ on remyelination and behavior in mice submitted to a chronicCPZ model. Mice were fed either control or CPZ(0.2% p/p) chow for twelve weeks, administered BLZ945 (200 mg/kg/day, oralgavage) or vehicle during ten weeks (C, BLZ945, CPZ and CPZ+BLZ945,respectively), and evaluated in the twelfth week of CPZ treatment. Although otherauthors reported CPZ-induced changes in locomotion and working memory, our preliminaryresults showed no significant differences across groups in open field,accelerated rotarod and locomotor activity behavior. In contrast, assays on MBPimmunoreactivity and NeuN+, AβPP+ and Neurotrace+ cell number showed significantdemyelination upon CPZ. In addition, a significant decrease was observed in neurodegenerationin CPZ+BLZ945 regarding CPZ mice. Positive results from these experiments couldbe transferred to the treatment of progressive forms of MS, an urgent and stillunmet medical need.