Tacrine(2)-ferulic acid, a novel multifunctional dimer, attenuates 6-hydroxydopamine-induced apoptosis in PC12 cells by activating Akt pathway |
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Authors: | Zhang Huan Mak Shinghung Cui Wei Li Wenming Han Renwen Hu Shengquan Ye Minzhong Pi Rongbiao Han Yifan |
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Affiliation: | aDepartment of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong;bLaboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China |
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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. |
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Keywords: | Abbreviations: AChE, acetylcholinesterase ERK, extracellular signal-regulated kinase GSK3β, glycogen synthase kinase 3β PI3-K, phosphoinositide 3-kinase ROS, reactive oxygen species PD, Parkinson&rsquo s disease 6-OHDA, 6-hydroxydopamine TnFA, tacrine(n)&ndash ferulic acid |
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