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.
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.
Ezoulin
M J M
MJ
Unité de Pharmacochimie Moléculaire et Systèmes Membranaires (EA2381), Université Paris 7-Denis Diderot, 75251 Paris cedex 05, France.
Liu
Z
Z
Dutertre-Catella
H
H
Wu
G
G
Dong
C Z
CZ
Heymans
F
F
Ombetta
J E
JE
Rat
P
P
Massicot
F
F
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*
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