title: Pharmacodynamic study of FS-0311: a novel highly potent, selective acetylcholinesterase inhibitor.
abstract: (1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311, a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance. PC12 cell injury was induced by beta-amyloid 25-35 (Abeta(25-35)), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase (AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against Abeta(25-35) peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising candidate in neurodegenerative diseases, such as Alzheimer's disease and Vascular dementia.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, P.R. China.
authors.forename: Zhi Fei
authors.initials: ZF
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Xi Can
authors.initials: XC
authors.lastname: Tang
authors.forename: Song
authors.initials: S
authors.lastname: Feng
authors.forename: Xu Chang
authors.initials: XC
authors.lastname: He
authors.forename: Dong Lu
authors.initials: DL
authors.lastname: Bai
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy*; D004365:Drugs, Chinese Herbal; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley