Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation
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 (RO...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/3/1062 |
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| author | Chiung-Mei Chen Chien-Yu Yen Wan-Ling Chen Chih-Hsin Lin Yih-Ru Wu Kuo-Hsuan Chang Guey-Jen Lee-Chen |
| author_facet | Chiung-Mei Chen Chien-Yu Yen Wan-Ling Chen Chih-Hsin Lin Yih-Ru Wu Kuo-Hsuan Chang Guey-Jen Lee-Chen |
| author_sort | Chiung-Mei Chen |
| collection | DOAJ |
| description | 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), <i>Glycyrrhiza inflata</i> (<i>G. inflata</i>, 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, <i>G. inflata,</i> and SG-Tang through mitigating α-synuclein-stimulated neuroinflammation in PD, as new drug candidates for PD treatment. |
| first_indexed | 2024-03-09T04:04:25Z |
| format | Article |
| id | doaj.art-42aff551a4ce40ea90127ece683cac5f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T04:04:25Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-42aff551a4ce40ea90127ece683cac5f2023-12-03T14:09:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-01223106210.3390/ijms22031062Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting NeuroinflammationChiung-Mei Chen0Chien-Yu Yen1Wan-Ling Chen2Chih-Hsin Lin3Yih-Ru Wu4Kuo-Hsuan Chang5Guey-Jen Lee-Chen6Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, TaiwanDepartment of Life Science, National Taiwan Normal University, Taipei 11677, TaiwanDepartment of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, TaiwanDepartment of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, TaiwanDepartment of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, TaiwanDepartment of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, TaiwanDepartment of Life Science, National Taiwan Normal University, Taipei 11677, TaiwanParkinson’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), <i>Glycyrrhiza inflata</i> (<i>G. inflata</i>, 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, <i>G. inflata,</i> and SG-Tang through mitigating α-synuclein-stimulated neuroinflammation in PD, as new drug candidates for PD treatment.https://www.mdpi.com/1422-0067/22/3/1062Parkinson’s disease/α-synucleinNLRP1/3IL-1β/IL-6IkBα/P65JNK/JUNP38/STAT1 |
| spellingShingle | Chiung-Mei Chen Chien-Yu Yen Wan-Ling Chen Chih-Hsin Lin Yih-Ru Wu Kuo-Hsuan Chang Guey-Jen Lee-Chen Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation International Journal of Molecular Sciences Parkinson’s disease/α-synuclein NLRP1/3 IL-1β/IL-6 IkBα/P65 JNK/JUN P38/STAT1 |
| title | Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation |
| title_full | Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation |
| title_fullStr | Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation |
| title_full_unstemmed | Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation |
| title_short | Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation |
| title_sort | pathomechanism characterization and potential therapeutics identification for parkinson s disease targeting neuroinflammation |
| topic | Parkinson’s disease/α-synuclein NLRP1/3 IL-1β/IL-6 IkBα/P65 JNK/JUN P38/STAT1 |
| url | https://www.mdpi.com/1422-0067/22/3/1062 |
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