Phenotypic shift of astrocytes from A1 to A2 induced by fasudil improves demyelination recovery in cuprizone-treated mice.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and subsequent axonal degeneration. Astrocytes (ASTs) play a dual role in MS pathogenesis, adopting either neurotoxic A1 or neuroprotective A2 phenotypes, which respectively inhibit or promote myelin repair. Fasudil (FSD), a Rho kinase inhibitor, has demonstrated potential in modulating AST phenotypes and facilitating remyelination. In this study, we investigated whether FSD treatment transformed astrocytes from A1 to A2 phenotype in cuprizone-induced demyelinating mice. Our results showed that FSD markedly suppressed A1 AST activation while enhancing A2 AST activation. Concurrently, FSD decreased pro-inflammatory chemokines such as CXCL1 and CXCL10, and increased A2-associated neurotrophic factors including BDNF and FGF2. These alterations fostered a favorable microenvironment that inhibited inflammatory responses and supported oligodendrocyte precursor cell (OPCs) differentiation and maturation, thereby ameliorated CPZ-induced demyelination. The study further revealed that these phenotypic transformation was mediated through the inhibition of NF-κB and LCN2 signaling pathways. This work identifies FSD as a promising therapeutic candidate for inhibiting demyelination through the regulation of AST polarization via specific signaling mechanism.