The treatment of
immunomodulation in
multiple sclerosis (MS) can alleviate the severity and relapses. However, it cannot improve the neurological disability of patients due to a lack of myelin protection and regeneration. Therefore, remyelinating
therapies may be one of the feasible strategies that can prevent axonal degeneration and restore neurological disability. Natural product
icariin (ICA) is a
flavonol compound extracted from epimedium
flavonoids, which has
neuroprotective effects in several models of neurological diseases. Here, we attempt to explore whether ICA has the potential to treat
demyelination and its possible mechanisms of action using
lipopolysaccharide-treated BV2 microglia, primary microglia, bone marrow-derived macrophages, and
cuprizone-induced
demyelination model. The indicators of oxidative stress and inflammatory response were evaluated using commercial kits. The results showed that ICA significantly reduced the levels of oxidative intermediates
nitric oxide,
hydrogen peroxide,
malondialdehyde, and inflammatory
cytokines TNF-α, IL-1β, and increased the levels of
antioxidants superoxide dismutase,
catalase,
glutathione peroxidase, and anti-inflammatory
cytokines IL-10 and TGF-β in vitro cell experiments. In vivo
demyelination model, ICA significantly alleviated the behavioral abnormalities and enhanced the integrated optical density/mm2 of
Black Gold II and
myelin basic protein myelin staining, accompanied by the inhibition of oxidative stress/inflammatory response. Immunohistochemical staining showed that ICA significantly induced the expression of nuclear factor erythroid derived 2/
heme oxygenase-1 (Nrf2/HO-1) and inhibited the expression of
toll-like receptor 4/
nuclear factor kappa B (TLR4/NF-κB), which are two key signaling pathways in
antioxidant and anti-inflammatory processes. Our results strongly suggest that ICA may be used as a potential agent to treat
demyelination via regulating Nrf2/HO-1-mediated antioxidative stress and TLR4/NF-κB-mediated inflammatory responses.