Study of PMS777, a new type of acetylcholinesterase inhibitor, in human HepG2 cells. Comparison with tacrine and galanthamine on oxidative stress and mitochondrial impairment.
Acetylcholinesterase inhibitors are commonly used as cognitive enhancers for dementia in aged people. Among them, tacrine (THA) but not galanthamine, was shown to exhibit hepatotoxicity which reduces its clinical use. PMS777, both a PAF antagonist and a new potent acetylcholinesterase inhibitor was recently demonstrated to reverse scopolamine-induced amnesia in mice without toxicity. In the present study, the effects of THA, galanthamine and PMS777 were compared in HepG2 cells on the oxidative parameters involved in the reported hepatotoxicity of THA. THA (> or = 10 microM) induced an oxidative stress as shown by elevated ROS and MDA production and by a decrease in GSH level. Moreover, mitochondrial membrane potential and redox status were decreased. At low concentrations (< or =10 microM), there was no significant disturbance. None of the oxidative stress markers was affected by PMS777 up to the maximum concentration tested and it is suggested that PMS777 is not cytotoxic for HepG2 cells. Galanthamine was also without cytotoxicity. Our results suggest that the toxic effect of THA above 10 microM may be caused by drug-induced mitochondrial energization impairment and destabilisation of membrane phospholipids associated with an oxidative stress. In contrast by preventing these dysfunctions, PMS777 could be safer than THA.
Ezoulin
M 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.
Dong
C Z
CZ
Liu
Z
Z
Li
J
J
Chen
H Z
HZ
Heymans
F
F
Lelièvre
L
L
Ombetta
J E
JE
Massicot
F
F
D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D005663:Furans / Q000633:toxicity*; D005702:Galantamine / Q000633:toxicity*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects*; D010972:Platelet Activating Factor / Q000502:physiology; D013619:Tacrine / Q000633:toxicity*
D002800:Cholinesterase Inhibitors; D005663:Furans; C507206:PMS 777; D010972:Platelet Activating Factor; D005702:Galantamine; D013619:Tacrine