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.
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.
Zhang
Hai Yan
HY
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.
Liang
Yan Qi
YQ
Tang
Xi Can
XC
He
Xu Chang
XC
Bai
Dong Lu
DL
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
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