Fasudil enhances the phagocytosis of myelin debris and the expression of neurotrophic factors in cuprizone-induced demyelinating mice.
Neurosci Lett
; 753: 135880, 2021 05 14.
Article
en En
| MEDLINE
| ID: mdl-33838256
ABSTRACT
Multiple sclerosis (MS) is mainly associated with the neuroinflammation and demyelination in the central nervous system (CNS), in which the failure of remyelination results in persistent neurological dysfunction. Fasudil, a typical Rho kinase inhibitor, has been exhibited beneficial effects on several models of neurodegenerative disorders. In this study, we showed that Fasudil promoted the uptake of myelin debris by microglia via cell experiments and through a cuprizone (CPZ)-induced demyelinating model. In vitro, microglia with phagocytic debris exhibited enhanced expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), and the conditioned medium promoted the maturation of oligodendrocyte precursor cells (OPCs). Meanwhile, Fasudil upregulated TREM2/DAP12 pathway, which positively regulated the phagocytosis of myelin debris by microglia. Similarly, in vivo, Fasudil intervention enhanced the clearance of myelin debris, upregulated the expression of BDNF and GDNF on microglia, and promoted the formation of Oligo2+/PDGFRα+ OPCs and the maturation of MBPâ¯+â¯oligodendrocytes in the brain. Our results showed that Fasudil targeted the phagocytic function of microglia, effectively clearing myelin debris produced during pathological process possibly by upregulating TREM2/DAP12 pathway, accompanied by increased expression of BDNF and GDNF. However, the precise mechanism underlying the effects of Fasudil in promoting phagocytic effects and neurotrophic factors remains to be elucidated.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Desmielinizantes
/
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina
/
Remielinización
/
Vaina de Mielina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Neurosci Lett
Año:
2021
Tipo del documento:
Article