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

Objective

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.

Methods

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.

Results

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.

Conclusion

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.