Astragaloside IV alleviates motor and anxiety deficits in Parkinson's disease mice by targeting TLR4.

Parkinson's disease (PD) is characterized by progressive motor dysfunction and non-motor symptoms (NMS), such as anxiety, which are poorly managed by current dopaminergic therapies. This study investigated the therapeutic potential of Astragaloside IV (AS-IV), a natural saponin with known anti-inflammatory properties, for simultaneously ameliorating motor and anxiety-like behaviors in PD by targeting Toll-like receptor 4 (TLR4)-mediated neuroinflammation. Using an MPTP-induced PD model in wild-type (WT) mice, we found that AS-IV administration dose-dependently improved motor coordination and reduced anxiety-like behaviors. Mechanistically, AS-IV directly bound to TLR4, inhibiting the TLR4/NF-κB signaling pathway in microglia within the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and hippocampus. This led to a reduction in pro-inflammatory cytokines and preserved the integrity of dopaminergic and hippocampal neurons. A critical finding was that all therapeutic effects of AS-IV were abolished in MPTP-treated TLR4-deficient (TLR4-/-) mice, unequivocally establishing TLR4 as the essential target. Our findings highlight AS-IV as a promising multi-symptom therapeutic candidate for PD, capable of addressing both motor and non-motor deficits through a unified anti-inflammatory mechanism.