Luteolin rescues myelin integrity and cognitive-motor function via Nrf2 pathway activation: a natural candidate vs. dimethyl fumarate in cuprizone-induced multiple sclerosis

<b>Objective:</b> Targeting the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway represents a promising therapeutic strategy for multiple sclerosis (MS). However, approved drugs like dimethyl fumarate (DMF) often induce severe side effects. This study investigated the natural flavonoid luteolin (LUT) as a potential dietary supplement alternative to DMF in a cuprizone (CPZ)-induced demyelination mouse model of MS.<b>Methods:</b> Mice were randomly assigned to five groups: control, CPZ model, CPZ+DMF (15 mg/kg), CPZ+LUT (25 mg/kg), and CPZ+LUT (50 mg/kg). Motor coordination and spatial memory were assessed via rotarod and Morris water maze tests. Myelin integrity was evaluated by Luxol fast blue staining and myelin basic protein (MBP) immunofluorescence/Western blot. Oxidative stress was measured by assessing superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels. Nrf2 pathway activation was analyzed by nuclear translocation of Nrf2 and expression of downstream proteins (HO-1, NQO1) via Western blot. Molecular docking simulated interactions between compounds and the Keap1 protein.<b>Results:</b> LUT treatment significantly restored motor coordination and spatial memory, with efficacy comparable to DMF. It promoted MBP expression, attenuated oxidative damage by modulating SOD, CAT, GSH-Px, and MDA levels, and preserved myelin integrity. Furthermore, LUT markedly facilitated Nrf2 nuclear translocation and upregulated HO-1 and NQO1 expression. Molecular docking indicated that LUT possessed stronger binding affinity to the target protein Keap1 and a lower potential for off-target toxicity compared to the primary active metabolite of DMF.<b>Conclusion:</b> Luteolin exerts significant neuroprotective effects, primarily via Nrf2 pathway activation, with efficacy parallel to DMF but a superior safety profile. These findings identify LUT as a promising natural compound, bridging functional foods and MS therapy, and provide a foundation for developing LUT-enriched dietary regimens as an adjunct treatment strategy for MS.