title: Tacrine(2)-ferulic acid, a novel multifunctional dimer, attenuates 6-hydroxydopamine-induced apoptosis in PC12 cells by activating Akt pathway.
abstract: Oxidative stress is closely related to the pathogenesis of neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the neuroprotective effect of tacrine-ferulic acid dimers linked by an alkylenediamine side chain (TnFA, n=2-7), a series of novel acetylcholinesterase inhibitors, against 6-hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells. Among these dimers, pre-treatment of tacrine(2)-ferulic acid (T2FA, 3-30 μM) attenuated 6-OHDA-induced apoptosis in a concentration-dependent manner. The activations of glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase (ERK) were observed after the treatment of 6-OHDA. Both SB415286 (an inhibitor of GSK3β) and PD98059 (an inhibitor of ERK kinase) reduced the neurotoxicity induced by 6-OHDA, indicating that GSK3β and ERK are involved in 6-OHDA-induced apoptosis. T2FA was able to inhibit the activation of GSK3β, but not ERK, in an Akt-dependent manner. Furthermore, LY294002, a phosphoinositide 3-kinase inhibitor, abolished the neuroprotective effect of T2FA. Collectively, these results suggest that T2FA prevents 6-OHDA-induced apoptosis possibly by activating the Akt pathway in PC12 cells.
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.forename: Shinghung
authors.initials: S
authors.lastname: Mak
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Wenming
authors.initials: W
authors.lastname: Li
authors.forename: Renwen
authors.initials: R
authors.lastname: Han
authors.forename: Shengquan
authors.initials: S
authors.lastname: Hu
authors.forename: Minzhong
authors.initials: M
authors.lastname: Ye
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Pi
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D004789:Enzyme Activation; D016627:Oxidopamine / Q000494:pharmacology*; D016716:PC12 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D003373:Coumaric Acids; D017382:Reactive Oxygen Species; D013619:Tacrine; D016627:Oxidopamine; C004999:ferulic acid; D051057:Proto-Oncogene Proteins c-akt