title: Bis(12)-hupyridone, a novel multifunctional dimer, promotes neuronal differentiation more potently than its monomeric natural analog huperzine A possibly through α7 nAChR.
abstract: The cause of many neurodegenerative disorders can be ascribed to the loss of functional neurons, and thus agents capable of promoting neuronal differentiation may have therapeutic benefits to patients of these disorders. In this study, the effects and underlying mechanisms of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase inhibitor modified from huperzine A (HA), on neuronal differentiation were investigated using both the rat PC12 pheochromocytoma cell line and adult rat hippocampus neural stem cells. B12H (3-30 μM), characterized by morphological changes and expression of GAP-43, induced neurite outgrowth in a concentration- and time-dependent manner, with almost 3-fold higher efficacy than that of HA in PC12 cells. Furthermore, B12H (2.5-10 μM), but not HA, promoted neuronal differentiation as shown by the percentage increase of βIII-tubulin positive neurons in neural stem cells. The activities of extracellular signal-regulated kinase (ERK), as well as its downstream transcription factors Elk-1 and cAMP response element-binding protein (CREB) were elevated in the B12H-treated PC12 cells. Mitogen-activated protein kinase kinase inhibitors and alpha7-nicotinic acetylcholine receptor (α7nAChR) antagonist blocked the neurite outgrowth and the activation of ERK induced by B12H. All these findings suggest that B12H potently induces pro-neuronal cells into differentiated neurons by activating the ERK pathway possibly via regulating α7nAChR. These findings support the recent proposition that α7nAChR is required for the neuronal dendritic arborization and differentiation in the adult mice hippocampus, and provide insights into the possible therapeutic potential of B12H in treating neurodegenerative disorders.
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Guo-Zhen
authors.initials: GZ
authors.lastname: Cui
authors.forename: Wenming
authors.initials: W
authors.lastname: Li
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shengquan
authors.initials: S
authors.lastname: Hu
authors.forename: Shinghung
authors.initials: S
authors.lastname: Mak
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
authors.forename: Chung-Lit
authors.initials: CL
authors.lastname: Choi
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Wong
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019281:Dimerization; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000470:Alkaloids; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D015363:Quinolones; D011978:Receptors, Nicotinic; D012717:Sesquiterpenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; C528260:bis(12)-hupyridone; C050426:huperzine A; D000110:Acetylcholinesterase