The Antihypertensive Guanabenz Exacerbates Integrated Stress Response and Disrupts the Brain Circadian Clock.
The Antihypertensive Guanabenz Exacerbates Integrated Stress Response and Disrupts the Brain Circadian Clock.
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DOI：
10.3390/clockssleep5040043
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发表时间：
2023-10-31
期刊：
影响因子：
3.1
通讯作者：
中科院分区：
文献类型：
--
作者：
生物钟调节着通常与太阳日同步的各种生物过程。昼夜节律紊乱与健康问题有关。了解细胞生理和代谢与昼夜节律相结合的信号机制将有助于开发新的治疗策略。整合应激反应(ISR)是由细胞应激源激活的，通过协调mRNA的翻译来维持生理动态平衡。在一些神经系统疾病中发现了异常的ISR，这些疾病表现出昼夜节律和睡眠被打乱。最近的工作已经开始揭示ISR在调节生物钟的生理方面的关键作用。2，6-二氯苯亚甲氨基胍乙酸酯(Ganabenz)是一种口服生物利用型α2-肾上腺素能受体激动剂，几十年来一直被用作抗高血压药物。最近的研究表明，愈创木酚对ISR有调节作用。在这里，我们使用多学科方法评估了吧那苯对细胞和行为昼夜节律的影响。我们发现，在培养的成纤维细胞和小鼠脑中，愈创木酚可以通过增加eIF2α的磷酸化来诱导间歇性休克反应。Ganabenz对eIF2α的过度磷酸化与细胞和动物的昼夜节律缩短以及小鼠的行为昼夜节律的扰乱有关。Ganabenz给药扰乱了小鼠视交叉上核(主要起搏器)中时钟蛋白PER1和PER2的昼夜振荡。这些结果揭示了Ganabenz在调节昼夜节律中的一个重要但先前未知的角色，并表明ISR激活加剧可以通过扰乱Clock基因的表达来损害大脑生物钟的功能。
The circadian clock regulates a variety of biological processes that are normally synchronized with the solar day. Disruption of circadian rhythms is associated with health problems. Understanding the signaling mechanisms that couple cell physiology and metabolism to circadian timekeeping will help to develop novel therapeutic strategies. The integrated stress response (ISR) is activated by the cellular stressors to maintain physiological homeostasis by orchestrating mRNA translation. Aberrant ISR has been found in a number of neurological diseases that exhibit disrupted circadian rhythms and sleep. Recent work has started to uncover a critical role for the ISR in regulating the physiology of the circadian clock. Guanabenz (2,6-dichlorobenzylidene aminoguanidine acetate) is an orally bioavailable α2-adrenergic receptor agonist that has been used as an antihypertensive for decades. Recent studies demonstrated that guanabenz can regulate the ISR. Here, we assessed the effects of guanabenz on cellular and behavioral circadian rhythms using a multidisciplinary approach. We found that guanabenz can induce the ISR by increasing eIF2α phosphorylation in cultured fibroblasts as well as in the mouse brain. The hyperphosphorylation of eIF2α by guanabenz is associated with the shortened circadian period in cells and animals and the disruption of behavioral circadian rhythms in mice. Guanabenz administration disrupted circadian oscillations of the clock protein Per1 and Per2 in the mouse suprachiasmatic nucleus, the master pacemaker. These results uncover a significant yet previously unidentified role of guanabenz in regulating circadian rhythms and indicate that exacerbated ISR activation can impair the functions of the brain’s circadian clock by disrupting clock gene expression.
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影响因子：
6.8
作者：
Singla, Rubal;Mishra, Abhishek;Cao, Ruifeng
通讯作者：
Cao, Ruifeng
影响因子：
16.2
作者：
Pathak, Salil Saurav;Liu, Dong;Cao, Ruifeng
通讯作者：
Cao, Ruifeng
影响因子：
4.5
作者：
Ramanathan C;Kathale ND;Liu D;Lee C;Freeman DA;Hogenesch JB;Cao R;Liu AC
通讯作者：
Liu AC
DOI：
10.1038/nrg2430
发表时间：
2008-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
25
作者：
Ma, Tao;Trinh, Mimi A.;Wexler, Alyse J.;Bourbon, Clarisse;Gatti, Evelina;Pierre, Philippe;Cavener, Douglas R.;Klann, Eric
通讯作者：
Klann, Eric