College of Pharmacy, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi 10326, Republic of Korea.
College of Pharmacy, Chungbuk National University, 194-21 Osongsaemyung-1-ro, Osong, Chungbuk 28160, Republic of Korea.
Int Immunopharmacol. 2020 Mar;80:106231. doi: 10.1016/j.intimp.2020.106231. Epub 2020 Jan 31.
Novel 1,2,3,4-tetrahydroquinoline derivatives with N-alkanoyl, N-benzoyl, or chlorobenzoyl substituents were designed and synthesized to inhibit nuclear factor-kappa B (NF-κB) known to be involved in the regulation of many immune and inflammatory responses. These compounds have been previously reported to inhibit NF-κB transcriptional activity in Raw 267.4 macrophage cells and exhibit cytotoxicities to several human cancer cell lines (Jo et al., ACS Med. Chem. Lett. 7 (2016) 385-390). Accumulating evidence indicated that NF-κB is also involved in neuroinflammation implicated in many neurodegenerative diseases. Thus, the present study investigated effects of 1,2,3,4-tetrahydroquinoline derivatives on LPS-stimulated inflammatory mediators and cell migration using BV2 microglial cells as a model. We found that seven compounds tested in this study inhibited LPS-induced pro-inflammatory mediators including interleukin-6, tumor necrosis factor-α, and nitric oxide in concentration-dependent manners. Among these compounds, ELC-D-2 exhibited the most potent inhibition without showing significant cytotoxicity. We also found that ELC-D-2 attenuated levels of LPS-induced inducible nitric oxide synthase and cyclooxygenase-2. Moreover, ELC-D-2 inhibited nuclear translocation of NF-κB by suppressing inhibitor of kappa Bα phosphorylation. Furthermore, ELC-D-2 inhibited LPS-induced activation of c-Jun N-terminal kinase (JNK), which was associated with suppression of inflammatory mediators and migration of LPS-treated BV2 cells. Collectively, our findings demonstrate that ELC-D-2 inhibits LPS-induced pro-inflammatory mediators and cell migration by suppressing NF-κB translocation and JNK phosphorylation in BV2 microglial cells. These results suggest that ELC-D-2 might have a beneficial impact on various brain disorders in which neuroinflammation involving microglial activation plays a crucial role in the pathogenesis of these diseases.
新型 1,2,3,4-四氢喹啉衍生物具有 N-烷酰基、N-苯甲酰基或氯苯甲酰基取代基，旨在抑制核因子-κB（NF-κB），已知 NF-κB 参与许多免疫和炎症反应的调节。这些化合物先前已被报道可抑制 Raw 267.4 巨噬细胞中的 NF-κB 转录活性，并对几种人癌细胞系具有细胞毒性（Jo 等人，ACS Med. Chem. Lett. 7（2016）385-390）。越来越多的证据表明，NF-κB 还参与许多神经退行性疾病中涉及的神经炎症。因此，本研究使用 BV2 小胶质细胞作为模型，研究了 1,2,3,4-四氢喹啉衍生物对 LPS 刺激的炎症介质和细胞迁移的影响。我们发现，在这项研究中测试的七种化合物以浓度依赖的方式抑制了 LPS 诱导的促炎介质，包括白细胞介素-6、肿瘤坏死因子-α和一氧化氮。在这些化合物中，ELC-D-2 表现出最强的抑制作用，而没有显示出明显的细胞毒性。我们还发现，ELC-D-2 减弱了 LPS 诱导的诱导型一氧化氮合酶和环氧化酶-2 的水平。此外，ELC-D-2 通过抑制 IκBα 磷酸化抑制 NF-κB 的核易位。此外，ELC-D-2 抑制了 LPS 诱导的 c-Jun N 末端激酶（JNK）的激活，这与抑制 LPS 处理的 BV2 细胞中的炎症介质和迁移有关。总之，我们的研究结果表明，ELC-D-2 通过抑制 NF-κB 易位和 JNK 磷酸化来抑制 LPS 诱导的 BV2 小胶质细胞中的促炎介质和细胞迁移。这些结果表明，ELC-D-2 可能对涉及小胶质细胞激活的神经炎症在这些疾病发病机制中起关键作用的各种脑疾病具有有益影响。
