Essential Role of Keap1-Nrf2 Signaling in Mood Disorders: Overview and Future Perspective.
Essential Role of Keap1-Nrf2 Signaling in Mood Disorders: Overview and Future Perspective.
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DOI：
10.3389/fphar.2018.01182
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发表时间：
2018
影响因子：
5.6
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Hashimoto K
抑郁症是最常见的情绪障碍之一，复发率很高。越来越多的证据表明，具有 CNC 同源性 (ECH) 相关蛋白 1 (Keap1) 的转录因子 Kelch 样红系细胞衍生蛋白 - 核因子（红系衍生 2）样 2 (Nrf2) 系统在抑郁症相关炎症中发挥着关键作用。临床前研究表明，抑郁样表型小鼠的前额皮质（PFC）、CA3和海马齿状回（DG）中Keap1和Nrf2的蛋白表达量低于对照小鼠。在习得性无助范式中，抑郁样表型大鼠海马 PFC 和 DG 中 Keap1 和 Nrf2 的蛋白水平也低于对照和恢复大鼠。此外，具有抑郁样表型的啮齿动物具有更高水平的促炎细胞因子。有趣的是，与野生型小鼠相比，Nrf2 敲除（KO）小鼠表现出抑郁样表型，并且血清促炎细胞因子水平更高。此外，与野生型小鼠相比，Nrf2 KO小鼠前额皮质、海马CA3和DG中脑源性神经营养因子（BDNF）的表达较低。 7,8-二羟基黄酮是一种 TrkB 激动剂，通过刺激 PFC、CA3 和 DG 中的 BDNF-TrkB，在 Nrf2 KO 小鼠中显示出抗抑郁作用。用萝卜硫素（一种天然存在的 Nrf2 激活剂）进行预处理，可以防止小鼠在炎症或慢性社交失败压力后出现抑郁样表型。有趣的是，在小鼠的幼年和青春期阶段，通过饮食摄入含有 0.1% 萝卜硫素（萝卜硫素的前体）的食物，可以预防成年期慢性社交失败压力后出现抑郁样表型。此外，重度抑郁症和双相情感障碍顶叶皮质中 Keap1 和 Nrf2 的蛋白表达低于对照组。这些发现表明 Keap1-Nrf2 系统在应激恢复中发挥着关键作用，而应激恢复与情绪障碍的病理生理学有关。因此，饮食中摄入包括萝卜硫苷（或SFN）在内的十字花科蔬菜可能可以预防或最大程度地减少抑郁症患者因压力和/或炎症引起的缓解后的复发。在这篇综述中，作者想讨论Keap1-Nrf2系统在情绪障碍中的作用。
Depression is one of the most common mood disorders with a high rate of relapse. Accumulating evidence suggests that the transcription factor Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1)-Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system plays a key role in inflammation which is involved in depression. Preclinical studies demonstrated that the protein expressions of Keap1 and Nrf2 in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of hippocampus in mice with depression-like phenotype were lower than control mice. In the learned helplessness paradigm, the protein levels of Keap1 and Nrf2 in the PFC and DG of hippocampus from rats with depression-like phenotype were also lower than control and resilient rats. Furthermore, rodents with depression-like phenotype have higher levels of pro-inflammatory cytokines. Interestingly, Nrf2 knock-out (KO) mice exhibit depression-like phenotype, and higher serum levels of pro-inflammatory cytokines compared with wild-type mice. Furthermore, Nrf2 KO mice have lower expression of brain-derived neurotrophic factor (BDNF) in the PFC, and CA3 and DG of hippocampus compared to wild-type mice. 7,8-Dihydroxyflavone, a TrkB agonist, showed antidepressant effects in Nrf2 KO mice, by stimulating BDNF-TrkB in the PFC, CA3, and DG. Pretreatment with sulforaphane, a naturally occurring Nrf2 activator, prevented depression-like phenotype in mice after inflammation, or chronic social defeat stress. Interestingly, dietary intake of 0.1% glucoraphanin (a precursor of sulforaphane) containing food during juvenile and adolescent stages of mice could prevent depression-like phenotype in adulthood after chronic social defeat stress. Moreover, the protein expressions of Keap1 and Nrf2 in the parietal cortex from major depressive disorder and bipolar disorder were lower than controls. These findings suggest that Keap1-Nrf2 system plays a key role in the stress resilience which is involved in the pathophysiology of mood disorders. It is, therefore, possible that dietary intake of cruciferous vegetables including glucoraphanin (or SFN) may prevent or minimize relapse from remission, induced by stress and/or inflammation in depressed patients. In the review, the author would like to discuss the role of Keap1-Nrf2 system in mood disorders.
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DOI：
10.1016/j.bbi.2015.06.001
发表时间：
2015-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Haapakoski R;Mathieu J;Ebmeier KP;Alenius H;Kivimäki M
通讯作者：
Kivimäki M
DOI：
10.1056/nejmoa1306033
发表时间：
2013-12-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
de Zeeuw D;Akizawa T;Audhya P;Bakris GL;Chin M;Christ-Schmidt H;Goldsberry A;Houser M;Krauth M;Lambers Heerspink HJ;McMurray JJ;Meyer CJ;Parving HH;Remuzzi G;Toto RD;Vaziri ND;Wanner C;Wittes J;Wrolstad D;Chertow GM;BEACON Trial Investigators
通讯作者：
BEACON Trial Investigators
影响因子：
3.6
作者：
El-Behadli, Ana F.;Sharp, Carla;Nicklas, Theresa A.
通讯作者：
Nicklas, Theresa A.
影响因子：
10.6
作者：
Dowlati, Yekta;Herrmann, Nathan;Lanctot, Krista L.
通讯作者：
Lanctot, Krista L.
影响因子：
5.6
作者：
Hashimoto K
通讯作者：
Hashimoto K