The Antihypertensive Guanabenz Exacerbates Integrated Stress Response and Disrupts the Brain Circadian Clock

IF 2.1 Q3 CLINICAL NEUROLOGY
Hao Lin, Muhammad Naveed, Aidan Hansen, Tracy G. Anthony, Ruifeng Cao
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Abstract

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.
降压药Guanabenz加重综合应激反应并扰乱大脑生物钟
生物钟调节着各种生物过程,这些过程通常与太阳日同步。昼夜节律紊乱与健康问题有关。了解将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。综合应激反应(integrated stress response, ISR)由细胞应激源激活,通过调控mRNA的翻译来维持生理稳态。在许多表现出昼夜节律和睡眠中断的神经系统疾病中发现了异常的ISR。最近的研究已经开始揭示ISR在调节生理时钟方面的关键作用。Guanabenz(2,6-二氯苄胺胍醋酸酯)是一种口服α2-肾上腺素能受体激动剂,几十年来一直被用作降压药。近年来的研究表明,胍苯胺可以调节ISR。在这里,我们使用多学科方法评估了胍那苯对细胞和行为昼夜节律的影响。我们发现,胍苯苯可以通过增加培养成纤维细胞和小鼠大脑中eIF2α的磷酸化来诱导ISR。guanabenz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行为昼夜节律的破坏有关。Guanabenz给药破坏了小鼠视交叉上核(主起搏器)中时钟蛋白Per1和Per2的昼夜节律振荡。这些结果揭示了guanabenz在调节昼夜节律中的重要作用,并且表明ISR激活加剧可以通过破坏生物钟基因表达来损害大脑生物钟的功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clocks & Sleep
Clocks & Sleep Multiple-
CiteScore
4.40
自引率
0.00%
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0
审稿时长
7 weeks
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