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

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.