Combination therapy with exosomes and NLRP3 inhibition enhances myelin repair in a cuprizone-induced demyelination model

Multiple sclerosis (MS), a chronic neuroinflammatory disorder, involves demyelination and neurodegeneration, necessitating therapies that currently target inflammation and enhance myelin repair. This study investigated the combined efficacy of mesenchymal stem cell (MSC)-derived exosomes (EXOs) and MCC950, an NLRP3 inflammasome inhibitor, in a cuprizone (CPZ)-induced demyelination mouse model. Thirty male C57BL/6J mice were assigned to five groups: healthy control, CPZ+Saline, CPZ+EXOs, CPZ+MCC950, and CPZ+EXOs+MCC950. Exosomes were isolated from rat bone marrow MSCs, characterized, and confirmed to localize to the brain via Dil staining. Over six weeks, CPZ-induced corpus callosum demyelination was followed by two weeks of treatment. Behavioral assessments (Y-maze), histopathology (FluoroMyelin, PLP/GFAP immunofluorescence), oxidative stress marker (MDA, TAC, SOD/CAT/GPx), and qRT‒PCR analyses of oligodendrocyte lineage, inflammatory, and antioxidant genes were performed. Behavioral improvements in spatial memory were comparable across treatments. Compared with monotherapy, combined EXOs-MCC950 therapy increased remyelination, as evidenced by elevated oligodendrocyte lineage markers (PDGFRα, Olig2, and MBP), reduced the extent of demyelination, and restored PLP expression. Neuroinflammation was suppressed via reduced astrocytes and proinflammatory cytokines expression (IL-1β, IL-18, and TNF-α). EXOs treatment upregulated Nrf2-driven antioxidant genes (HO-1, NQO1, and Nrf2), whereas MCC950 restored antioxidant enzyme activity (MDA/TAC/CAT/SOD/GPx). These findings demonstrate that combining EXOs with MCC950 improves myelin repair via attenuating inflammation and oxidative stress.