Colony‐stimulating factor‐1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model

WIES MANCINI, VICTORIA S. B.; DI PIETRO, ANABELLA A.; OLMOS, SOLEDAD; SILVA PINTO, PABLO; VENCE, MARIANELA; MARDER, MARIEL; IGAZ, LIONEL M.; MARCORA, MARÍA S.; PASQUINI, JUANA M.; CORREALE, JORGE D.; PASQUINI, LAURA A.

JOURNAL OF NEUROCHEMISTRY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2022

0022-3042

Multiple sclerosis (MS), especially in its progressive phase, involves early axonal andneuronal damage resulting from a combination of inflammatory mediators, demyelination,and loss of trophic support. During progressive disease stages, a microenvironmentis created within the central nervous system (CNS) favoring the arrival andretention of inflammatory cells. Active demyelination and neurodegeneration havealso been linked to microglia (MG) and astrocyte (AST)-activationin early lesions.While reactive MG can damage tissue, exacerbate deleterious effects, and contributeto neurodegeneration, it should be noted that activated MG possess neuroprotectivefunctions as well, including debris phagocytosis and growth factor secretion. Theprogressive form of MS can be modeled by the prolonged administration to cuprizone(CPZ) in adult mice, as CPZ induces highly reproducible demyelination of differentbrain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and ASTactivation and axonal damage. Therefore, our goal was to evaluate the effects of areduction in microglial activation through orally administered brain-penetrantcolony-stimulatingfactor-1receptor (CSF-1R)inhibitor BLZ945 (BLZ) on neurodegenerationand its correlation with demyelination, astroglial activation, and behavior in a chronicCPZ-induceddemyelination model. Our results show that BLZ treatment successfullyreduced the microglial population and myelin loss. However, no correlation was foundbetween myelin preservation and neurodegeneration, as axonal degeneration wasmore prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offsetCPZ-inducedbe taken into account when proposing the modulation of microglial activation in thedesign of therapies relevant for demyelinating diseases.astroglial activation and behavioral alterations. These results should