Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson's Disease Targeting...

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons and the presence of α-synuclein-containing Lewy bodies. The unstructured α-synuclein forms insoluble fibrils and aggregates that result in increased reactive oxygen species (ROS) and cellular toxicity in PD. Neuroinflammation engaged by microglia actively contributes to the pathogenesis of PD. In this study, we showed that VB-037 (a quinoline compound), glycyrrhetic acid (a pentacyclic triterpenoid), Glycyrrhiza inflata (G. inflata, a Chinese herbal medicine), and Shaoyao Gancao Tang (SG-Tang, a formulated Chinese medicine) suppressed the nitric oxide (NO) production and interleukin (IL)-1β maturation in α-synuclein-stimulated BV-2 cells. Mouse inflammation antibody array further revealed increased IL-1α, IL-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) expression in α-synuclein-inflamed BV-2 cells and compound pretreatment effectively reduced the expression and release of these pro-inflammatory mediators. The test compounds and herbal medicines further reduced α-synuclein aggregation and associated oxidative stress, and protected cells against α-synuclein-induced neurotoxicity by downregulating NLR family pyrin domain containing 1 (NLRP1) and 3 (NLRP3), caspase 1, IL-1β, IL-6, and associated nuclear factor (NF)-κB inhibitor alpha (IκBα)/NF-κB P65 subunit (P65), c-Jun N-terminal kinase (JNK)/proto-oncogene c-Jun (JUN), mitogen-activated protein kinase 14 (P38)/signal transducer and activator of transcription 1 (STAT1) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways in dopaminergic neurons derived from α-synuclein-expressing SH-SY5Y cells. Our findings indicate the potential of VB-037, glycyrrhetic acid, G. inflata, and SG-Tang through mitigating α-synuclein-stimulated neuroinflammation in PD, as new drug candidates for PD treatment.