title: 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.
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy. Electronic address: mirko.magnone@unige.it.
authors.forename: Mirko
authors.initials: M
authors.lastname: Magnone
authors.forename: Sonia
authors.initials: S
authors.lastname: Scarfì
authors.forename: Laura
authors.initials: L
authors.lastname: Sturla
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Guida
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.forename: Annalisa
authors.initials: A
authors.lastname: Salis
authors.forename: Antonio
authors.initials: A
authors.lastname: De Flora
authors.forename: Elena
authors.initials: E
authors.lastname: Zocchi
mesh_terms: D000040:Abscisic Acid / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006540:Herbicides / Q000494:pharmacology / Q000627:therapeutic use; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D015054:Zymosan
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006540:Herbicides; D016328:NF-kappa B; D011728:Pyridones; D012333:RNA, Messenger; C013351:fluridone; D000040:Abscisic Acid; D015054:Zymosan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D015232:Dinoprostone
keywords: Inflammation; Lymphocyte; Monocyte; Monocyte chemoattractant protein-1; Nuclear factor-κB; Prostaglandin-E(2)