Abstract
FSD-C10, a Fasudil derivative, was shown to reduce severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through the modulation of the immune response and induction of neuroprotective molecules in the central nervous system (CNS). However, whether FSD-C10 can promote neuroregeneration remains unknown. In this study, we further analyzed the effect of FSD-C10 on neuroprotection and remyelination. FSD-C10-treated mice showed a longer, thicker and more intense MAP2 and synaptophysin positive signal in the CNS, with significantly fewer CD4+ T cells, macrophages and microglia. Importantly, the CNS of FSD-C10-treated mice showed a shift of activated macrophages/microglia from the type 1 to type 2 status, elevated numbers of oligodendrocyte precursor cells (OPCs) and oligodendrocytes, and increased levels of neurotrophic factors NT-3, GDNF and BDNF. FSD-C10-treated microglia significantly inhibited Th1/Th17 cell differentiation and increased the number of IL-10+ CD4+ T cells, and the conditioned medium from FSD-C10-treated microglia promoted OPC survival and oligodendrocyte maturation. Addition of FSD-C10 directly promoted remyelination in a chemical-induced demyelination model on organotypic slice culture, in a BDNF-dependent manner. Together, these findings demonstrate that FSD-C10 promotes neural repair through mechanisms that involved both immunomodulation and induction of neurotrophic factors.
Highlights
From M1- to M2-dominant polarization of microglia is a desirable strategy for efficient remyelination therapies
Extensive CD4+ T cells and CD68+ macrophages were found in brains from untreated EAE mice whereas the frequency of these cells were significantly reduced in mice treated with nasal FSD-C10 (Figure S2)
Given that FSD-C10 stimulated the production of the neurotrophic factors NT-3, GDNF and BDNF in vivo (Fig. 4), we aimed to evaluate whether these proteins played a role in FSD-C10-induced remyelination
Summary
From M1- to M2-dominant polarization of microglia is a desirable strategy for efficient remyelination therapies. Failure of spontaneous remyelination is associated with a lack of sufficient amount of neurotrophic factors (BDNF, NT-3 and GDNF) in the CNS during inflammation[16,17,18]. In this context, our previous study showed that nasal administration of FSD-C10, a derivative of Fasudil with less toxic effect, effectively suppressed the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found that FSD-C10 significantly promoted neurological recovery, oligodendrogenesis, and remyelination The mechanisms underlying these effects relayed on immunomodulation and direct neuroregeneration. Our data show that FSD-C10 has a beneficial effect on EAE acting through the modulation of the immune response and neuroregeneration
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