title: Stereoselectivities of enantiomers of huperzine A in protection against beta-amyloid(25-35)-induced injury in PC12 and NG108-15 cells and cholinesterase inhibition in mice.
abstract: Recently, the potent cholinesterase inhibitor (-)-huperzine A (HupA) was demonstrated to protect neuronal and glial cells against the cytotoxicity of beta-amyloid (Abeta). Since the unnatural (+)-HupA is a much less potent inhibitor, it was of interest to examine the stereoselectivity of cellular protection by the two isomers. In the present study, effects of (+)- and (-)-HupA on Abeta(25-35)-induced injury were compared in PC12 and NG108-15 neuroblastoma cell lines. Following a 24 h exposure to 1 microM Abeta(25-35), cell survival was markedly reduced, but preincubation with (+)-HupA or (-)-HupA (0.1-10 microM) enhanced survival significantly. The potency of (-)-HupA and (+)-HupA in protecting against Abeta toxicity was similar. This result contrasted with the stereoselectivity of cholinesterase inhibition in vitro and in vivo, in which (-)-HupA is about 50-fold more potent than (+)-HupA. It is concluded that the neuroprotective properties of HupA enantiomers have no relation to anti-cholinesterase activity.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Tai Yuan Road, Shanghai 200031, PR China.
authors.forename: Hai Yan
authors.initials: HY
authors.lastname: Zhang
authors.forename: Yan Qi
authors.initials: YQ
authors.lastname: Liang
authors.forename: Xi Can
authors.initials: XC
authors.lastname: Tang
authors.forename: Xu Chang
authors.initials: XC
authors.lastname: He
authors.forename: Dong Lu
authors.initials: DL
authors.lastname: Bai
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000470:Alkaloids; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D012717:Sesquiterpenes; C074636:amyloid beta-protein (25-35); C050426:huperzine A; D000109:Acetylcholine