Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status.
Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status.
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DOI：
10.3390/antiox10111811
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发表时间：
2021-11-15
期刊：
影响因子：
--
通讯作者：
Feng Z
中科院分区：
文献类型：
--
作者：
Cui Y;Xiong Y;Li H;Zeng M;Wang Y;Li Y;Zou X;Lv W;Gao J;Cao R;Meng L;Long J;Liu J;Feng Z
NF-E2相关因子2（Nrf 2）是II相酶的关键转录调节因子，被认为对神经元保护有益。我们之前设计了一种新的查耳酮类似物，1-（2，3，4-三甲氧基苯基）-2-（3，4，5-三甲氧基苯基）-丙烯酮（Tak），其可以在体外特异性激活Nrf 2。在这里，我们报告说，Tak赋予显着的海马神经元保护在体外和体内。用Tak处理对培养的神经元细胞没有显著毒性。相反，Tak通过增加线粒体功能增加细胞ATP产生，并通过激活Nrf 2介导的II相酶表达降低活性氧水平。Tak预处理可防止谷氨酸诱导的兴奋性神经元死亡，并伴有线粒体呼吸抑制、超氧化物产生增加和细胞凋亡激活。进一步的研究表明，Tak的保护作用是由Akt信号通路介导的。同时，Tak给药可通过降低海马氧化应激充分消除东莨菪碱诱导的认知障碍。此外，在高脂饮食下的能量应激小鼠模型中也观察到一致的益处，因为Tak的施用显著增加Akt信号传导介导的抗氧化酶表达并防止海马神经元凋亡，而对小鼠代谢状态没有显著影响。总体而言，我们的研究表明，Tak通过Akt介导的Nrf 2活化来保护认知功能，以维持体内和体外的氧化还原状态，这表明Tak是一种有前途的治疗氧化性神经元疾病的药理学候选物。
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.
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