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

ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons and the presence of ?-synuclein-containing Lewy bodies. The unstructured ?-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)-1? maturation in ?-synuclein-stimulated BV-2 cells. Mouse inflammation antibody array further revealed increased IL-1?, IL-1?, tumor necrosis factor (TNF)-?, interferon (IFN)-?, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) expression in ?-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 ?-synuclein aggregation and associated oxidative stress, and protected cells against ?-synuclein-induced neurotoxicity by downregulating NLR family pyrin domain containing 1 (NLRP1) and 3 (NLRP3), caspase 1, IL-1?, IL-6, and associated nuclear factor (NF)-?B inhibitor alpha (I?B?)/NF-?B 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 ?-synuclein-expressing SH-SY5Y cells. Our findings indicate the potential of VB-037, glycyrrhetic acid, G. inflata, and SG-Tang through mitigating ?-synuclein-stimulated neuroinflammation in PD, as new drug candidates for PD treatment.

SUBMITTER: Chen CM

PROVIDER: S-EPMC7865530 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Chen Chiung-Mei CM Yen Chien-Yu CY Chen Wan-Ling WL Lin Chih-Hsin CH Wu Yih-Ru YR Chang Kuo-Hsuan KH Lee-Chen Guey-Jen GJ

International journal of molecular sciences 20210121 3

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 ...[more]

PMID: 33494411

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Project description:Parkinson's disease (PD) is a progressive neurodegenerative disorder that is diagnosed largely on clinical grounds due to characteristic motor manifestations that result from the loss of nigrostriatal dopaminergic neurons. While traditional pharmacological approaches to enhance dopamine levels, such as with L-dopa, can be very effective initially, the chronic use of this dopamine precursor is commonly plagued with motor response complications. Additionally, with advancing disease, non-motor manifestations emerge, including psychosis and dementia that compound patient disability. The pathology includes hallmark intraneuronal inclusions known as Lewy bodies and Lewy neurites that contain fibrillar α-synuclein aggregates. Evidence has also accumulated that these aggregates can propagate across synaptically connected brain regions, a phenomenon that can explain the progressive nature of the disease and the emergence of additional symptoms over time. The level of α-synuclein is believed to play a critical role in its fibrillization and aggregation. Accordingly, nucleic acid-based therapeutics for PD include strategies to deliver dopamine biosynthetic enzymes to boost dopamine production or modulate the basal ganglia circuitry in order to improve motor symptoms. Delivery of trophic factors that might enhance the survival of dopamine neurons is another strategy that has been attempted. These gene therapy approaches utilize viral vectors and are delivered stereotaxically in the brain. Alternative disease-modifying strategies focus on downregulating the expression of the α-synuclein gene using various techniques, including modified antisense oligonucleotides, short hairpin RNA, short interfering RNA, and microRNA. The latter approaches also have implications for dementia with Lewy bodies. Other PD genes can also be targeted using nucleic acids. In this review, we detail these various strategies that are still experimental, and discuss the challenges and opportunities of nucleic acid-based therapeutics for PD.

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

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

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