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

PABLO SILVA PINTO; MARIEL MARDER; JUANA MARÍA PASQUINI1; LIONEL MULLER IGAZ; VICTORIA SOFÍA BERENICE WIES MANCINI1; JORGE DANIEL CORREALE2; LAURA ANDREA PASQUINI1.

Córdoba, Córdoba, Argentina

Congreso; XXXIII CONGRESO ANUAL SAN 2018 CORDOBA ? ARGENTINA; 2018

Cuprizone (CPZ)-induced demyelination 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 and neurodegeneration processes and are physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R) signaling. The aim of this study is to evaluate the effects of BLZ945 ‒a CSF-1R inhibitor which significantly reduces the number of MG‒ on remyelination and behavior in mice submitted to a chronic CPZ model. Mice were fed either control or CPZ (0.2% p/p) chow for twelve weeks, administered BLZ945 (200 mg/kg/day, oral gavage) or vehicle during ten weeks (C, BLZ945, CPZ and CPZ+BLZ945, respectively), and evaluated in the twelfth week of CPZ treatment. Although other authors reported CPZ-induced changes in locomotion and working memory, our preliminary results showed no significant differences across groups in open field, accelerated rotarod and locomotor activity behavior. In contrast, assays on MBP immunoreactivity and NeuN+, AβPP+ and Neurotrace+ cell number showed significant demyelination upon CPZ. In addition, a significant decrease was observed in neurodegeneration in CPZ+BLZ945 regarding CPZ mice. Positive results from these experiments could be transferred to the treatment of progressive forms of MS, an urgent and still unmet medical need.