Polysaccharide Ameliorates Parkinson's Disease by Enhancing Dopamine Levels, Inhibiting NLRP3 Inflammasome Activation, and Promoting Mitochondrial Autophagy.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic (DA) neuron loss and neuroinflammation. Current therapies fail to halt disease progression, which underscores the need for new treatments. This study investigated the neuroprotective effects and mechanisms of Gastrodia elata polysaccharide (GEP) in MPTP-induced PD mice. GEP was administered for two weeks, and motor function was assessed using behavioral tests. Immunohistochemical and Western Blot analyses evaluated DA neuron survival, microglial activation, and NLRP3 inflammasome components. GEP-medicated serum (GMS) was applied to SH-SY5Y neuroblastoma cells exposed to neuroinflammatory conditions, and metabolomic analysis identified key metabolites. GEP improved motor function, reduced DA neuron loss, and increased tyrosine hydroxylase expression. It suppressed microglial activation, decreased NLRP3 inflammasome components, and lowered pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). GMS reduced ROS levels, enhanced mitochondrial membrane potential, and promoted autophagy in SH-SY5Y cells. Metabolomic analysis revealed elevated dopamine levels in GMS, linked to NLRP3 inflammasome inhibition, and reduced neuroinflammation. GMS also activated the PINK1/Parkin pathway to promote mitochondrial autophagy and prevent apoptosis. GEP alleviates PD symptoms by targeting neuroinflammation, mitochondrial dysfunction, and dopamine regulation, which highlights its potential as a therapeutic candidate. Further research is needed to explore its long-term efficacy and clinical applications.