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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.

Research paper by M J M MJ Ezoulin, Z Z Liu, H H Dutertre-Catella, G G Wu, C Z CZ Dong, F F Heymans, J E JE Ombetta, P P Rat, F F Massicot

Indexed on: 13 Nov '07Published on: 13 Nov '07Published in: International Immunopharmacology



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.