Ginsenoside Rg1Attenuates Neuroinflammation in Parkinson’sDisease Models via Concomitant Modulation of Canonical and NoncanonicalWnt Pathways in Microglial M1/M2 Polarization

Microglial-mediated neuroinflammation is a core driver of brain disorders. Thus, modulating microglial activity is a critical therapeutic goal. In this study, we explored how Ginsenoside Rg1 (Rg1) protects against the inflammation seen in Parkinson’s disease (PD). Our experiments utilized MPTP-challenged mice and lipopolysaccharide (LPS)-stimulated BV2 cells. Our data show that Rg1 restores motor function and preserves dopaminergic neurons in the substantia nigra. Notably, Rg1 treatment reconfigures the neuroinflammatory milieu, characterized by the targeted suppression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and a reciprocal elevation of the anti-inflammatory marker (IL-10). This effect stems from a precise rebalancing of Wnt signaling. Rg1 activates the Wnt3a/β-catenin pathway while suppressing the Wnt5a/ROR2/JNK axis. Such regulation promotes the transition of microglia to a protective M2 phenotype. When we knocked down Wnt3a and ROR2 using siRNA, the benefits of Rg1 were largely lost. In short, Rg1 alleviates neuroinflammation by recalibrating Wnt signals, offering a potential strategy for PD intervention.