Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status

NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 i...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Yuting Cui, Yue Xiong, Hua Li, Mengqi Zeng, Yan Wang, Yuan Li, Xuan Zou, Weiqiang Lv, Jing Gao, Ruijun Cao, Lingjie Meng, Jiangang Long, Jiankang Liu, Zhihui Feng
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
Materias:
Akt
Acceso en línea:https://doaj.org/article/8df8bef1c35f4d4a98dffc370f1fddb5
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:8df8bef1c35f4d4a98dffc370f1fddb5
record_format dspace
spelling oai:doaj.org-article:8df8bef1c35f4d4a98dffc370f1fddb52021-11-25T16:28:55ZChalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status10.3390/antiox101118112076-3921https://doaj.org/article/8df8bef1c35f4d4a98dffc370f1fddb52021-11-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1811https://doaj.org/toc/2076-3921NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases.Yuting CuiYue XiongHua LiMengqi ZengYan WangYuan LiXuan ZouWeiqiang LvJing GaoRuijun CaoLingjie MengJiangang LongJiankang LiuZhihui FengMDPI AGarticlephase II enzymesNrf2Akthippocampusmitochondrial functionTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1811, p 1811 (2021)
institution DOAJ
collection DOAJ
language EN
topic phase II enzymes
Nrf2
Akt
hippocampus
mitochondrial function
Therapeutics. Pharmacology
RM1-950
spellingShingle phase II enzymes
Nrf2
Akt
hippocampus
mitochondrial function
Therapeutics. Pharmacology
RM1-950
Yuting Cui
Yue Xiong
Hua Li
Mengqi Zeng
Yan Wang
Yuan Li
Xuan Zou
Weiqiang Lv
Jing Gao
Ruijun Cao
Lingjie Meng
Jiangang Long
Jiankang Liu
Zhihui Feng
Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status
description NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases.
format article
author Yuting Cui
Yue Xiong
Hua Li
Mengqi Zeng
Yan Wang
Yuan Li
Xuan Zou
Weiqiang Lv
Jing Gao
Ruijun Cao
Lingjie Meng
Jiangang Long
Jiankang Liu
Zhihui Feng
author_facet Yuting Cui
Yue Xiong
Hua Li
Mengqi Zeng
Yan Wang
Yuan Li
Xuan Zou
Weiqiang Lv
Jing Gao
Ruijun Cao
Lingjie Meng
Jiangang Long
Jiankang Liu
Zhihui Feng
author_sort Yuting Cui
title Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status
title_short Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status
title_full Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status
title_fullStr Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status
title_full_unstemmed Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status
title_sort chalcone-derived nrf2 activator protects cognitive function via maintaining neuronal redox status
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/8df8bef1c35f4d4a98dffc370f1fddb5
work_keys_str_mv AT yutingcui chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT yuexiong chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT huali chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT mengqizeng chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT yanwang chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT yuanli chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT xuanzou chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT weiqianglv chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT jinggao chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT ruijuncao chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT lingjiemeng chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT jianganglong chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT jiankangliu chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
AT zhihuifeng chalconederivednrf2activatorprotectscognitivefunctionviamaintainingneuronalredoxstatus
_version_ 1718413150345232384