Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan.
Aging (Albany NY). 2020 Nov 10;12(23):23619-23646. doi: 10.18632/aging.103700.
Polyglutamine (polyQ)-mediated spinocerebellar ataxias (SCA) are caused by mutant genes with expanded CAG repeats encoding polyQ tracts. The misfolding and aggregation of polyQ proteins result in increased reactive oxygen species (ROS) and cellular toxicity. Inflammation is a common manifestation of oxidative stress and inflammatory process further reduces cellular antioxidant capacity. Increase of activated microglia in the pons of SCA type 3 (SCA3) patients suggests the involvement of neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of indole compound NC009-1, 4-aminophenol-arachidonic acid derivative AM404, quinoline compound VB-037 and chalcone-coumarin derivative LM-031 using human HMC3 microglia and SCA3 ATXN3/Q-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing NO, IL-1β, TNF-α and IL-6 production and CD68 expression of IFN-γ-activated HMC3 microglia. In retinoic acid-differentiated ATXN3/Q-GFP SH-SY5Y cells inflamed with IFN-γ-primed HMC3 conditioned medium, treatment with the tested compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced polyQ aggregation and ROS and/or promoted neurite outgrowth. Examination of IL-1β- and TNF-α-mediated signaling pathways revealed that the tested compounds decreased IκBα/P65, JNK/JUN and/or P38/STAT1 signaling. The study results suggest the potential of NC009-1, AM404, VB-037 and LM-031 in treating SCA3 and probable other polyQ diseases.
多聚谷氨酰胺（polyQ）介导的脊髓小脑共济失调（SCA）是由编码多聚 Q 片段的突变基因引起的，这些基因的 CAG 重复序列扩展。多聚 Q 蛋白的错误折叠和聚集导致活性氧（ROS）和细胞毒性增加。炎症是氧化应激和炎症过程的常见表现，进一步降低了细胞的抗氧化能力。SCA 3 型（SCA3）患者桥脑部位激活的小胶质细胞增加表明神经炎症参与了疾病的发病机制。在这项研究中，我们使用人 HMC3 小胶质细胞和 SCA3 ATXN3/Q-GFP SH-SY5Y 细胞评估了吲哚化合物 NC009-1、4-氨基苯酚-花生四烯酸衍生物 AM404、喹啉化合物 VB-037 和查尔酮-香豆素衍生物 LM-031 的抗炎潜力。四种测试化合物通过抑制 NO、IL-1β、TNF-α 和 IFN-γ 激活的 HMC3 小胶质细胞产生的 IL-6 以及 CD68 表达显示出抗炎活性。在 IFN-γ 预刺激的 HMC3 条件培养基诱导的分化的 ATXN3/Q-GFP SH-SY5Y 细胞中，用测试化合物处理减轻了 caspase 1 活性和乳酸脱氢酶释放的增加，减少了多聚 Q 聚集和 ROS，或促进了神经元突起的生长。对 IL-1β 和 TNF-α 介导的信号通路的检测表明，测试化合物降低了 IκBα/P65、JNK/JUN 和/或 P38/STAT1 信号。研究结果表明，NC009-1、AM404、VB-037 和 LM-031 具有治疗 SCA3 和其他可能的多聚 Q 疾病的潜力。
