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The Anti-inflammatory Effects of 4-((5-Bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic Acid in Lipopolysaccharide-Activated Primary Microglial Cells

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Abstract

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.

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Funding

This study was supported by the National Natural Science Foundation of China (81701170, 81630028), the Natural Science Foundation of Jiangsu Province of China (BK20170122), the Science and Technology Department of Jiangsu Province (BE2016610), and Jiangsu Province Key Medical Discipline (ZDXKA2016020).

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Author notes

  1. Xiang Cao and Yuexinzi Jin contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China

    Xiang Cao, Yuexinzi Jin, He Zhang, Linjie Yu, Xinyu Bao & Yun Xu

  2. Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, Jiangsu, 210008, People’s Republic of China

    Xiang Cao, Yuexinzi Jin, He Zhang, Linjie Yu, Xinyu Bao & Yun Xu

  3. Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 211166, People’s Republic of China

    Fei Li

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  1. Xiang Cao
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Correspondence to Yun Xu.

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Cao, X., Jin, Y., Zhang, H. et al. The Anti-inflammatory Effects of 4-((5-Bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic Acid in Lipopolysaccharide-Activated Primary Microglial Cells. Inflammation 41, 530–540 (2018). https://doi.org/10.1007/s10753-017-0709-z

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