Department of Neurology, Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China.
Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, Jiangsu, 210008, People's Republic of China.
Inflammation. 2018 Mar;41(2):530-540. doi: 10.1007/s10753-017-0709-z.
Over-activated microglial cells are known to be implicated in various neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. Our previous reports have shown that ZL006, a compound with a hydrophobic ring A and a hydrophilic ring B with a carboxyl group, exhibited stronger neuroprotective activity in vitro and in vivo. However, the directly anti-inflammatory effects of these compounds in the central nervous system (CNS) have not been elucidated. In the present study, as a part of our ongoing screening experiment to evaluate the anti-inflammatory effects of new compounds, a newly synthesized 4-((5-bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid (LX007) was used to examine whether it could reduce the inflammatory responses of activated microglia. Our results indicated that LX007 inhibited lipopolysaccharide (LPS)-stimulated nitric oxide (NO) and prostaglandin E2 (PGE2) expression, as well as their regulatory gene-inducible NO syntheses (iNOS) and cyclooxygenase-2 (COX-2) in LPS-treated primary microglia. LPS-induced production from microglia of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF-α) was also significantly attenuated by LX007. Mechanistically, LX007 potently suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) p65 nuclear translocation in LPS-induced microglia. We therefore conclude that LX007 exhibits anti-inflammatory effects in LPS-stimulated microglial cells by inhibiting pro-inflammatory mediators corresponding to the downregulating of MAPKs and NF-κB activation. Taken together, the present study indicated that LX007 may have potential to be developed into an anti-inflammatory agent in the future.
过度激活的小胶质细胞被认为与各种神经退行性疾病有关，如阿尔茨海默病（AD）、帕金森病（PD）和多发性硬化症。我们之前的报告表明，ZL006 是一种具有疏水性环 A 和带有羧基的亲水性环 B 的化合物，在体外和体内均表现出更强的神经保护活性。然而，这些化合物在中枢神经系统（CNS）中的直接抗炎作用尚未阐明。在本研究中，作为我们正在进行的评估新化合物抗炎作用的筛选实验的一部分，使用新合成的 4-((5-溴-3-氯-2-羟基苄基)氨基)-2-羟基苯甲酸（LX007）来检查它是否可以减轻激活的小胶质细胞的炎症反应。我们的结果表明，LX007 抑制脂多糖（LPS）刺激的一氧化氮（NO）和前列腺素 E2（PGE2）表达，以及它们的调节基因诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）在 LPS 处理的原代小胶质细胞中。LX007 还显著减弱了 LPS 诱导的小胶质细胞中白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子（TNF-α）的产生。从机制上讲，LX007 强烈抑制 LPS 诱导的小胶质细胞中丝裂原激活蛋白激酶（MAPKs）和核因子-κB（NF-κB）p65 核易位的磷酸化。因此，我们得出结论，LX007 通过抑制 MAPKs 和 NF-κB 激活的下调来抑制促炎介质，从而在 LPS 刺激的小胶质细胞中发挥抗炎作用。综上所述，本研究表明，LX007 将来可能有潜力开发成一种抗炎药物。
