Potential Therapeutic Effects of Astragaloside IV in Parkinson's Disease Models via Modulation of...

Finding a new drug to slow or reverse the progression of Parkinson's disease (PD) is a significant step forward. Astragaloside Ⅳ (AS-Ⅳ) has been shown to have neuroprotective and anti-inflammatory properties, but its therapeutic effects and mechanisms in PD remain to be determined. Unilateral injection of rotenone (ROT) into the substantia nigra pars compacta (SNpc) was used to establish an in vivo model of PD. AS-Ⅳ intraperitoneal injection (IP) (40 mg/kg once/day for 14 days) was administered 6 weeks after modeling. Behavioral assessments were conducted using the limb hanging test, rotarod test, and gastrointestinal motility evaluations. The expression and localization of alpha-synuclein (α-syn) /γH2AX/STING/IFNα/βRα were explored using western blotting and confocal laser scanning microscopy. In vitro, ROT-treated BV2 microglial cells were used to mimic PD-associated neuroinflammation, and AS-Ⅳ was added 6 h post-ROT exposure. Genetic overexpression of A53T/A30P mutant α-syn was performed to investigate α-syn aggregation and pathway activation. AS-Ⅳ treatment significantly improved motor performance, reduced gastrointestinal dysfunction, and protected against DA neuron loss. The application of AS-Ⅳ inhibited α-syn aggregation and decreased the expression of γH2AX, STING, and IFNα/βRα in vivo and in vitro. The use of a STING inhibitor (H151) or agonist (2,3-cGAMP) confirmed that the α-syn-γH2AX-STING-IFN-I axis played a critical role in PD progression. AS-Ⅳ also restored ROT-induced loss of BV2 cell viability. In ROT-based PD in vivo and in vitro models, and α-syn mutant-mediated cell models, the α-syn-γH2AX-STING-IFN-I axis was activated, and α-syn aggregation was the upstream regulatory protein of STING. AS-Ⅳ might exert therapeutic effects via the α-syn-γH2AX-STING-IFN-I axis.