title: A new acetylcholinesterase inhibitor with anti-PAF activity modulates oxidative stress and pro-inflammatory mediators release in stimulated RAW 264.7 macrophage cells. Comparison with tacrine.
abstract: Inflammatory injury and induction of oxidative stress have been implicated as causative factors in neurodegenerative diseases such as Alzheimer's disease (AD). Using LPS-stimulated RAW 264.7 macrophages as a model of inflammatory injury, LPS was found to stimulate ROS production (159%), GSH depletion (15%) and loss of mitochondrial activity (32%) as well as TNFalpha release (40%), and NO production (13.7 times), all parameters involved in AD. PMS777, a tetrahydrofuran derivative, designed as a dual PAF and acetylcholinesterase inhibitor, was found to decrease ROS (up to 32%) and NO production (up to 5 times), TNFalpha release (33%). PMS777 also prevents loss of mitochondrial activity, and GSH depletion. In contrast, tacrine was found to decrease ROS production (57% up to 102%) and TNFalpha level (up to 30%). It decreases NO release only at the highest concentrations without preventing loss of mitochondrial activity and GSH depletion. In this study, we show that PMS777 is strongly anti-inflammatory against LPS-induced responses in RAW 264.7. Differential effects between PMS777 and tacrine could be attributed to the anti-PAF activity of PMS777 which was able to fight inflammatory events and oxidative injury whereas tacrine only minimizes them. PMS777 could open a new approach in the treatment of AD.
authors.affiliation: Unité de Pharmacochimie Moléculaire et Systèmes Membranaires (EA2381), Université Paris 7-Denis Diderot, 75251 Paris cedex 05, France.
authors.forename: M J M
authors.initials: MJ
authors.lastname: Ezoulin
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Dutertre-Catella
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.forename: C Z
authors.initials: CZ
authors.lastname: Dong
authors.forename: F
authors.initials: F
authors.lastname: Heymans
authors.forename: J E
authors.initials: JE
authors.lastname: Ombetta
authors.forename: P
authors.initials: P
authors.lastname: Rat
authors.forename: F
authors.initials: F
authors.lastname: Massicot
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002843:Chromatin / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D005663:Furans / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013619:Tacrine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D002800:Cholinesterase Inhibitors; D002843:Chromatin; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; C507206:PMS 777; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013619:Tacrine; D005978:Glutathione; D015232:Dinoprostone