Colony-stimulating factor-1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model.
J Neurochem
; 160(6): 643-661, 2022 03.
Article
em En
| MEDLINE
| ID: mdl-34935149
ABSTRACT
Multiple sclerosis (MS), especially in its progressive phase, involves early axonal and neuronal damage resulting from a combination of inflammatory mediators, demyelination, and loss of trophic support. During progressive disease stages, a microenvironment is created within the central nervous system (CNS) favoring the arrival and retention of inflammatory cells. Active demyelination and neurodegeneration have also been linked to microglia (MG) and astrocyte (AST)-activation in early lesions. While reactive MG can damage tissue, exacerbate deleterious effects, and contribute to neurodegeneration, it should be noted that activated MG possess neuroprotective functions as well, including debris phagocytosis and growth factor secretion. The progressive form of MS can be modeled by the prolonged administration to cuprizone (CPZ) in adult mice, as CPZ induces highly reproducible demyelination of different brain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and AST activation and axonal damage. Therefore, our goal was to evaluate the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation, and behavior in a chronic CPZ-induced demyelination model. Our results show that BLZ treatment successfully reduced the microglial population and myelin loss. However, no correlation was found between myelin preservation and neurodegeneration, as axonal degeneration was more prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offset CPZ-induced astroglial activation and behavioral alterations. These results should be taken into account when proposing the modulation of microglial activation in the design of therapies relevant for demyelinating diseases. Cover Image for this issue https//doi.org/10.1111/jnc.15394.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Desmielinizantes
/
Esclerose Múltipla
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Argentina