Differential effect of PMS777, a new type of acetylcholinesterase inhibitor, and galanthamine on oxidative injury induced in human neuroblastoma SK-N-SH cells.
In the search for highly selective and potent cholinesterase inhibitors (AChEI) being able to improve oxidative injury, PMS777, a tetrahydrofuran derivative, was designed as a novel dual PAF and acetylcholinesterase inhibitor. The aim of this study was to investigate the modulatory effects of PMS777 and galanthamine, another AChEI, on the oxidative injury induced in neuronal cells. The SK-N-SH cells stimulated with LPS+IL-(1beta) were selected to investigate the direct inhibitory effect of PMS777 and galanthamine. LPS+IL-(1beta) induced oxidative injury as assessed by ROS production (29%), GSH depletion (11%) and loss of mitochondrial activity (22%). GSH depletion was never decreased by either drug. In contrast, ROS production and mitochondrial activity were totally prevented by addition of PMS777 but not galanthamine. PMS777 also inhibits butylcholinesterase and it shows selectivity for acetylcholinesterase. Thus, this PAF antagonist inaugurates a new type of AChEI, able to fight oxidative injury. Therefore, PMS777 could be of interest on patients with cognitive impairments and inflammatory damage, as in AD.
Ezoulin
Miezan J-M
MJ
Unité de Pharmacochimie Moléculaire et Systèmes Membranaires (EA2381), Université Paris 7-Denis Diderot, Case 7066, 2 Place Jussieu, 75251 Paris Cedex 05, France.
Li
Juan
J
Wu
Guirong
G
Dong
Chang-Zhi
CZ
Ombetta
Jean-Edouard
JE
Chen
Hong-Zhuan
HZ
Massicot
France
F
Heymans
Françoise
F
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002091:Butyrylcholinesterase / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D005702:Galantamine / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008928:Mitochondria / Q000187:drug effects; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D005663:Furans; D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; C507206:PMS 777; D010972:Platelet Activating Factor; D017382:Reactive Oxygen Species; D005702:Galantamine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D005978:Glutathione