Erjingwan Alleviates Parkinson's Disease via Activation of PPARA-Mediated Autophagy.

Abstract

Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal degeneration and neuroinflammation. Traditional Chinese medicine (TCM) formulas exhibit potential neuroprotective effects, yet the active components and underlying mechanisms of Erjingwan (EJW) remain unclear. To elucidate the therapeutic mechanisms of EJW in PD by integrating network pharmacology with in vivo and in vitro experimental validation. PD mice were modeled using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral assessments, histological staining, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and Western blotting were performed to evaluate neuronal injury, inflammation, and apoptosis. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify EJW components. Network pharmacology and machine learning were applied to screen potential targets. Molecular docking and molecular dynamics simulations were conducted to assess component-target interactions. Adeno-associated virus (AAV)-mediated peroxisome proliferator-activated receptor alpha (PPARA) knockdown in vivo and short hairpin RNA (shRNA) interference in vitro were used for mechanistic validation. EJW significantly improved motor dysfunction in PD mice. EJW attenuated dopaminergic neuronal loss in the substantia nigra, suppressed neuroinflammation, and decreased cell apoptosis. LC-MS/MS identified 10 bioactive compounds. Integrated analysis yielded 83 potential targets, with PPARA identified as a key target by machine learning. Molecular docking and dynamics simulations indicated stable binding between multiple bioactive compounds and PPARA. EJW upregulated PPARA expression and promoted autophagy. PPARA knockdown inhibited autophagy and diminished the neuroprotective effects of EJW. EJW alleviates PD by activating PPARA-mediated autophagy. PPARA may serve as a critical therapeutic target of EJW in PD.