Fluridone as a new anti-inflammatory drug

Abstract

Fluridone is a herbicide extensively utilized in agriculture for its documented safety in animals. Fluridone contains a 4(1H)-pyridone and a trifluoromethyl-benzene moiety, which are also present in molecules with analgesic and anti-inflammatory properties. The established absence of adverse effects of Fluridone on animals prompted us to investigate whether it could represent a new anti-inflammatory compound targeting human cells. In stimulated human monocytes, micromolar Fluridone inhibited cyclooxygenase-2 expression and the release of monocyte chemoattractant protein-1 and prostaglandin-E2, to a similar extent as Acetylsalicylic acid. Fluridone also inhibited the proliferation of aortic smooth muscle cells and reduced proliferation and cytokine release by human activated lymphocytes. The mechanism of Fluridone seems to rely on the dose-dependent inhibition of the nuclear translocation of nuclear factor-κB, a transcription factor playing a pivotal role in inflammation. Fluridone also inhibited the release from stimulated human monocytes of abscisic acid, a plant stress hormone recently discovered also in mammalian cells, where it stimulates pro-inflammatory responses. Interestingly, the mechanism of Fluridone's toxicity in plants relies on the inhibition of the enzyme phytoene desaturase, involved in the biosynthetic pathway of ß-carotene, the precursor of absciscic acid in plants. Finally, administration of Fluridone reduced peritoneal inflammation in Zymosan-treated mice. These results suggest that Fluridone could represent a new prototype of anti-inflammatory drug, also active on abscisic acid pro-inflammatory pathway.

Keywords: Inflammation; Lymphocyte; Monocyte; Monocyte chemoattractant protein-1; Nuclear factor-κB; Prostaglandin-E(2).