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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

Summary Aims 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...

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Published in:CNS neuroscience & therapeutics 2014-09, Vol.20 (9), p.840-850
Main Authors: Chao, Xiao‐Juan, Chen, Zi‐Wei, Liu, An‐Min, He, Xi‐Xin, Wang, Shao‐Gui, Wang, Yu‐Ting, Liu, Pei‐Qing, Ramassamy, Charles, Mak, Shing‐Hung, Cui, Wei, Kong, Ah‐Ng, Yu, Zhi‐Ling, Han, Yi‐Fan, Pi, Rong‐Biao
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container_end_page 850
container_issue 9
container_start_page 840
container_title CNS neuroscience & therapeutics
container_volume 20
creator Chao, Xiao‐Juan
Chen, Zi‐Wei
Liu, An‐Min
He, Xi‐Xin
Wang, Shao‐Gui
Wang, Yu‐Ting
Liu, Pei‐Qing
Ramassamy, Charles
Mak, Shing‐Hung
Cui, Wei
Kong, Ah‐Ng
Yu, Zhi‐Ling
Han, Yi‐Fan
Pi, Rong‐Biao
description Summary Aims 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. Methods and 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.
doi_str_mv 10.1111/cns.12286
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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. Methods and 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.</description><identifier>ISSN: 1755-5930</identifier><identifier>ISSN: 1755-5949</identifier><identifier>EISSN: 1755-5949</identifier><identifier>DOI: 10.1111/cns.12286</identifier><identifier>PMID: 24922524</identifier><language>eng</language><publisher>England: John Wiley &amp; Sons, Inc</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Alzheimer's disease ; Animals ; Apoptosis ; Caffeic Acids - pharmacology ; Cell death ; Cell Death - drug effects ; Cell Line, Transformed ; Cytoskeletal Proteins - metabolism ; Glutamic Acid - pharmacology ; Heme Oxygenase-1 - metabolism ; HO‐1 ; Humans ; Kelch-Like ECH-Associated Protein 1 ; Life Sciences ; Membrane Potential, Mitochondrial - drug effects ; Mice ; Neurobiology ; Neurons ; Neurons - drug effects ; Neurons and Cognition ; NF-E2-Related Factor 2 - metabolism ; Nootropic Agents - pharmacology ; Nrf2 ; Original ; Oxidative stress ; Oxidative Stress - drug effects ; Reactive Oxygen Species - metabolism ; RNA, Messenger - metabolism ; RNA, Small Interfering - pharmacology ; Signal Transduction - drug effects ; T3CA ; Tacrine - pharmacology ; Transfection</subject><ispartof>CNS neuroscience &amp; therapeutics, 2014-09, Vol.20 (9), p.840-850</ispartof><rights>2014 John Wiley &amp; Sons Ltd</rights><rights>2014 John Wiley &amp; Sons Ltd.</rights><rights>Copyright © 2014 John Wiley &amp; Sons Ltd</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493203/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493203/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,11562,27924,27925,46052,46476,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://onlinelibrary.wiley.com/doi/abs/10.1111%2Fcns.12286$$EView_record_in_Wiley-Blackwell$$FView_record_in_$$GWiley-Blackwell</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24922524$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://riip.hal.science/pasteur-01135506$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Chao, Xiao‐Juan</creatorcontrib><creatorcontrib>Chen, Zi‐Wei</creatorcontrib><creatorcontrib>Liu, An‐Min</creatorcontrib><creatorcontrib>He, Xi‐Xin</creatorcontrib><creatorcontrib>Wang, Shao‐Gui</creatorcontrib><creatorcontrib>Wang, Yu‐Ting</creatorcontrib><creatorcontrib>Liu, Pei‐Qing</creatorcontrib><creatorcontrib>Ramassamy, Charles</creatorcontrib><creatorcontrib>Mak, Shing‐Hung</creatorcontrib><creatorcontrib>Cui, Wei</creatorcontrib><creatorcontrib>Kong, Ah‐Ng</creatorcontrib><creatorcontrib>Yu, Zhi‐Ling</creatorcontrib><creatorcontrib>Han, Yi‐Fan</creatorcontrib><creatorcontrib>Pi, Rong‐Biao</creatorcontrib><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</title><title>CNS neuroscience &amp; therapeutics</title><addtitle>CNS Neurosci Ther</addtitle><description>Summary Aims 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. Methods and 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. 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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. Methods and 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.</abstract><cop>England</cop><pub>John Wiley &amp; Sons, Inc</pub><pmid>24922524</pmid><doi>10.1111/cns.12286</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
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subjects Adaptor Proteins, Signal Transducing - metabolism
Alzheimer's disease
Animals
Apoptosis
Caffeic Acids - pharmacology
Cell death
Cell Death - drug effects
Cell Line, Transformed
Cytoskeletal Proteins - metabolism
Glutamic Acid - pharmacology
Heme Oxygenase-1 - metabolism
HO‐1
Humans
Kelch-Like ECH-Associated Protein 1
Life Sciences
Membrane Potential, Mitochondrial - drug effects
Mice
Neurobiology
Neurons
Neurons - drug effects
Neurons and Cognition
NF-E2-Related Factor 2 - metabolism
Nootropic Agents - pharmacology
Nrf2
Original
Oxidative stress
Oxidative Stress - drug effects
Reactive Oxygen Species - metabolism
RNA, Messenger - metabolism
RNA, Small Interfering - pharmacology
Signal Transduction - drug effects
T3CA
Tacrine - pharmacology
Transfection
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
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