title: Protection of PMS777, a new AChE inhibitor with PAF antagonism, against amyloid-beta-induced neuronal apoptosis and neuroinflammation.
abstract: Amyloid-beta (Abeta) plays a central role in the neuroinflammation and cholinergic neuronal apoptosis in Alzheimer's disease, and thus has been considered as a main determinant of this disease. In the previous study, we reported that PMS777, a novel bis-interacting ligand for acetylcholinesterase (AChE) inhibition and platelet-activating factor (PAF) receptor antagonism, could significantly attenuate PAF-induced neurotoxicity. Continuing our efforts, we further investigated the protective effect of PMS777 on Abeta-induced neuronal apoptosis in vitro and neuroinflammation in vivo. PMS777 (1-100 microM) was found to inhibit Abeta-induced human neuroblastoma SH-SY5Y cell apoptosis in a concentration-dependent manner. Concurrently, PMS777 increased ratio of bcl-2 to bax mRNA, and inhibited both mRNA expression and activity of caspase-3 in SH-SY5Y cells after the exposure with Abeta. In vivo experimental study demonstrated that PMS777 could attenuate Abeta-induced microglial and astrocytic activation in the rat hippocampus after systemic administration. These results suggest that PMS777 potently protects against Abeta-induced neuronal apoptosis and neuroinflammation, and warrants further investigations in connection with its potential value in the treatment of Alzheimer's disease.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Jinjia
authors.initials: J
authors.lastname: Hu
authors.forename: Biyun
authors.initials: B
authors.lastname: Shao
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Cui
authors.forename: Changzhi
authors.initials: C
authors.lastname: Dong
authors.forename: Jean-Marc Miezan
authors.initials: JM
authors.lastname: Ezoulin
authors.forename: Xu
authors.initials: X
authors.lastname: Zhu
authors.forename: Wenlong
authors.initials: W
authors.lastname: Ding
authors.forename: Françoise
authors.initials: F
authors.lastname: Heymans
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D005663:Furans; C507206:PMS 777; D010972:Platelet Activating Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053148:Caspase 3