title: Effect of tacrine-3-caffeic acid, a novel multifunctional anti-Alzheimer's dimer, against oxidative-stress-induced cell death in HT22 hippocampal neurons: involvement of Nrf2/HO-1 pathway.
abstract: OBJECTIVE
  Oxidative stress (OS) plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). This study was designed to uncover the cellular and biochemical mechanisms underlying the neuroprotective effects of tacrine-3-caffeic acid (T3CA), a novel promising multifunctional anti-Alzheimer's dimer, against OS-induced neuronal death.
  
  
  RESULTS
  T3CA protected HT22 cells against high-concentration-glutamate-induced cell death in time- and concentration-dependent manners and potently attenuated glutamate-induced intracellular reactive oxygen species (ROS) production as well as mitochondrial membrane-potential (ΔΨ) disruption. Besides, T3CA significantly induced nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and increased its transcriptional activity, which were demonstrated by Western blotting, immunofluorescence, and antioxidant response element (ARE)-luciferase reporter gene assay. Further studies showed that T3CA potently up-regulated heme oxygenase-1 (HO-1), an endogenous antioxidative enzyme and a downstream effector of Nrf2, at both mRNA and protein levels. The neuroprotective effects of T3CA were partially reversed by brusatol, which reduced protein level of Nrf2, or by inhibiting HO-1 with siRNA or ZnPP-IX, a specific inhibitor of HO-1.
  
  
  CONCLUSIONS
  Taken together, these results clearly demonstrate that T3CA protects neurons against OS-induced cell death partially through Nrf2/ARE/HO-1 signaling pathway, which further supports that T3CA might be a promising novel therapeutic agent for OS-associated diseases.
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Chao
authors.forename: Zi-Wei
authors.initials: ZW
authors.lastname: Chen
authors.forename: An-Min
authors.initials: AM
authors.lastname: Liu
authors.forename: Xi-Xin
authors.initials: XX
authors.lastname: He
authors.forename: Shao-Gui
authors.initials: SG
authors.lastname: Wang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Wang
authors.forename: Pei-Qing
authors.initials: PQ
authors.lastname: Liu
authors.forename: Charles
authors.initials: C
authors.lastname: Ramassamy
authors.forename: Shing-Hung
authors.initials: SH
authors.lastname: Mak
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Ah-Ng
authors.initials: AN
authors.lastname: Kong
authors.forename: Zhi-Ling
authors.initials: ZL
authors.lastname: Yu
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Han
authors.forename: Rong-Biao
authors.initials: RB
authors.lastname: Pi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013619:Tacrine / Q000494:pharmacology*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002109:Caffeic Acids; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D018697:Nootropic Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D013619:Tacrine; D051547:Heme Oxygenase-1; C040048:caffeic acid
keywords: Cell death; HO-1; Nrf2; Oxidative stress; T3CA