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

Chiung-Mei Chen,Chih-Hsin Lin,Chien-Yu Yen,Wan-Ling Chen,Kuo-Hsuan Chang,Guey-Jen Lee-Chen,Yih-Ru Wu

doi:10.3390/ijms22031062

Abstract

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.

Highlights

IntroductionAlpha-synuclein (SNCA), parkin RBR E3 ubiquitin protein ligase (PRKN), parkinsonism associated deglycase (DJ1), PTEN induced kinase 1 (PINK1), leucine rich repeat kinase 2 (LRRK2), ATPase cation transporting 13A2
We proposed that α-synuclein can be up-taken by microglia to activate microglia, which will release IL-1β, IL-6, and tumor necrosis factor (TNF)-α and can activate nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 1 (NLRP1) and NLR family pyrin domain containing 3 (NLRP3) in Parkinson’s disease (PD) cellular models, both of which contribute to neuronal cytotoxicity
We explored if these Chinese herbal medicines (CHMs) or compounds exert their effects through mitigating the NLRP1/3, caspase 1, IL-1β, IL-6, and associated IκBα/P65, Jun N-terminal kinase (JNK)/JUN, P38/signal transducer and activator of transcription 1 (STAT1), and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways

Summary

Introduction

Alpha-synuclein (SNCA), parkin RBR E3 ubiquitin protein ligase (PRKN), parkinsonism associated deglycase (DJ1), PTEN induced kinase 1 (PINK1), leucine rich repeat kinase 2 (LRRK2), ATPase cation transporting 13A2. Have been identified to be the causative genes for familiar and early-onset PD (EOPD) [2]. Owing to the discovery of the causative genes, several pathogenic pathways were identified, which includes accumulation of aberrant or misfolded proteins, mitochondrial dysfunction, increased oxidative stress, impaired ubiquitin-proteasome function, failure of autophagy-lysosome and mitophagy, deficits in endosomal trafficking and inflammation (see review in [3]). Several genome wide-association studies (GWAS) have identified novel genetic associations with PD and these genes are linked to the previously known pathogenic pathways as well as other less recognized pathways, such as endocytosis, transcriptional dysregulation, inflammation, and cytokine-mediated signaling [4,5]

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