Co-administration of quercetin and NLRP3 inhibitor attenuates inflammation and oxidative stress in cuprizone-induced demyelination model.

Quercetin (Qur), as a natural plant-derived flavonoid with antioxidant and neuroprotective properties, and MCC950, a selective NLRP3 inflammasome inhibitor, have each demonstrated notable pharmacological activities, including antioxidant and anti-inflammatory effects. The present study examined the combined impacts of Qur and MCC950 on oxidative stress, demyelination, and inflammation in the cuprizone (CPZ)-induced demyelination model. To induce demyelination, CPZ (0.2% w/w) was incorporated into the normal diet of male C57BL/6 mice for 42 days. Subsequently, animals received Qur (25 mg/kg/day, oral), MCC950 (5 mg/kg/day, i.p), or their combination for 14 days. Working memory was evaluated using the Y-maze test. FluoroMyelin staining and GFAP immunofluorescence were used to assess the extent of demyelination and astrocyte activation, respectively. Oxidative stress and antioxidant biomarkers, including MDA, TOS, TAC, SOD, CAT, and GPx, were measured using colorimetric techniques. The expression levels of oligodendrocyte markers, antioxidant signaling, and pro-inflammatory cytokines, including MBP, PDGFRα, Olig2, Nrf2, HO-1, NQO1, GSK3β, IL-1β, IL-18, and TNF-α, were assessed by qRT-PCR. Our results indicated that co-administration of Qur and MCC950 improved working memory and restored antioxidant capacity. A significant reduction was found in the extent of demyelination, astrocytic reactivity, and inflammatory mediator expression in treated mice. Moreover, combined treatment elevated the expression levels of pro-myelinating and antioxidant markers more effectively than either agent alone. Our findings indicate that inhibiting the NLRP3 inflammasome and enhancing antioxidant defenses promote remyelination and confer neuroprotective effects by reducing oxidative stress and inflammation, likely through modulation of glial responses.