Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, Taiwan.
Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
Int J Mol Sci. 2021 Jan 21;22(3):1062. doi: 10.3390/ijms22031062.
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), inflata ( 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, inflata, and SG-Tang through mitigating α-synuclein-stimulated neuroinflammation in PD, as new drug candidates for PD treatment.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是多巴胺能（DAergic）神经元丧失和含有α-突触核蛋白的路易体的存在。无结构的α-突触核蛋白形成不溶性纤维和聚集体，导致 PD 中活性氧（ROS）和细胞毒性增加。小胶质细胞激活的神经炎症积极促进 PD 的发病机制。在这项研究中，我们表明 VB-037（一种喹啉化合物）、甘草酸（一种五环三萜）、inflata（inflata，一种中药）和芍药甘草汤（SG-Tang，一种配方中药）抑制了α-突触核蛋白刺激的 BV-2 细胞中一氧化氮（NO）的产生和白细胞介素（IL）-1β的成熟。小鼠炎症抗体阵列进一步显示，在α-突触核蛋白激活的 BV-2 细胞中，白细胞介素（IL）-1α、IL-1β、肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ、IL-6、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和粒细胞集落刺激因子（G-CSF）的表达增加，而化合物预处理有效降低了这些促炎介质的表达和释放。测试化合物和草药进一步减少了α-突触核蛋白的聚集和相关的氧化应激，并通过下调 NOD 样受体家族含pyrin 域蛋白 1（NLRP1）和 3（NLRP3）、半胱天冬酶 1、白细胞介素（IL）-1β、白细胞介素（IL）-6 和相关核因子（NF）-κB 抑制剂α（IκBα）/NF-κB P65 亚基（P65）、c-Jun N 末端激酶（JNK）/原癌基因 c-Jun（JUN）、丝裂原活化蛋白激酶 14（P38）/信号转导和转录激活因子 1（STAT1）和 Janus 激酶 2（JAK2）/信号转导和转录激活因子 3（STAT3）途径，来保护多巴胺能神经元免受源自α-突触核蛋白表达的 SH-SY5Y 细胞的神经毒性。我们的研究结果表明，VB-037、甘草酸、inflata 和 SG-Tang 通过减轻 PD 中α-突触核蛋白刺激的神经炎症，具有成为 PD 治疗新药物候选物的潜力。
