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...

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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:	phase II enzymes Nrf2 Akt hippocampus mitochondrial function Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/8df8bef1c35f4d4a98dffc370f1fddb5
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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
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Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status

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