Stigmasterol upregulates PDGFRα, contributing to white matter protection and anxiolytic-like behavior in a mouse model of vanadium-induced demyelination.

Demyelinating lesions, or plaques, can form around axons when mature oligodendrocytes are damaged, often because of viral infections, heavy metal toxicity, or autoimmune disorders. These lesions are associated with cognitive impairment, motor dysfunction, sensory deficits, and memory loss, and may contribute to the progression of neurodegenerative diseases. At present, no therapy exists for demyelinating disorders, and available treatments primarily slow the progression of myelin loss while cognitive and functional deficits persist. In this study, we investigated the neuroprotective potential of stigmasterol in a vanadium-induced demyelination. Forty-eight C57BL/6 mice were randomly assigned to three groups and received either saline, vanadium, or vanadium plus stigmasterol for 4 weeks. Behavioral assessments included the elevated plus maze and open field test for anxiety-like behavior, the Barnes maze for learning and memory, and grip strength and rotarod tests for motor function. Immunofluorescence staining and Western blotting were used to evaluate markers of oligodendrocyte lineage (Olig2, PDGFRα), myelin integrity (MBP, MOG, electron microscopy), neuronal survival (NeuN), and glial activation, while inflammatory cytokines (TNF-α, IL-6) were quantified by ELISA. Our results revealed that vanadium administration induced anxiety-like behavior, impaired behavioral flexibility, reduced motor strength and coordination, and was associated with loss of MBP and MOG expression, decreased PDGFRα and Olig2, and elevated glial activation and inflammatory cytokines. Remarkably, stigmasterol co-treatment ameliorated these behavioral deficits, preserved MBP and MOG expression, increased PDGFRα and Olig2 levels, and attenuated microglial and astrocytic activation along with TNF-α and IL-6 production. These findings suggest that stigmasterol confers neuroprotection by preserving oligodendrocyte lineage cells, enhancing PDGFRα-mediated precursor recruitment, and maintaining myelin integrity. By mitigating neuroinflammation and promoting remyelination, stigmasterol is a promising therapeutic candidate for metal-induced demyelinating disorders.