17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model
17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model
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在雄性衰老小鼠模型中，17β-雌二醇调节SIRT1并停止氧化应激介导的认知损伤
DOI：
10.3390/cells8080928
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发表时间：
2019-08-01
期刊：
影响因子：
6
通讯作者：
Kim, Myeong Ok
中科院分区：
文献类型：
--
作者：
Khan, Mehtab;Ullah, Rahat;Kim, Myeong Ok
氧化应激被认为是神经退行性疾病和正常衰老过程中的主要介质。一些研究已经报道，活性氧（ROS）的积累、氧化应激升高和神经炎症导致细胞功能障碍。这些病症导致与衰老相关的神经退行性疾病如阿尔茨海默病（AD）和帕金森病中的神经元细胞死亡。长期给予d-半乳糖（d-gal）10周会导致ROS产生和神经炎症，最终导致认知障碍。在这项研究中，我们评估了雌激素受体α（ER α）/沉默交配型信息调节2同源物1（SIRT 1）依赖性抗氧化剂的疗效，17 β-雌二醇对d-半乳糖诱导的氧化损伤介导的认知功能障碍的雄性小鼠模型。结果表明，17 β-雌二醇，通过刺激ER α/SIRT 1，停止d-半乳糖诱导的氧化应激介导的JNK/NF-？B过表达、神经炎症和神经元凋亡。此外，17 β-雌二醇改善d-半乳糖诱导的AD样病理生理学，突触功能障碍和记忆障碍的成年小鼠大脑。有趣的是，用Ex 527（一种有效的选择性SIRT 1抑制剂）抑制SIRT 1进一步增强了d-半乳糖诱导的毒性，并消除了17 β-雌二醇的有益作用。最重要的是，我们的分子对接研究首次揭示了17 β-雌二醇变构增加SIRT 1的表达，并消除了d-ga的抑制潜力。总之，我们可以得出结论，17 β-雌二醇，在ER α/SIRT 1依赖性的方式，废除d-gal诱导的氧化应激介导的记忆障碍，神经炎症，和神经退行性变的成年小鼠。
Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell death in aging-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease. Chronic administration of d-galactose (d-gal) for a period of 10 weeks causes ROS generation and neuroinflammation, ultimately leading to cognitive impairment. In this study, we evaluated the estrogen receptor alpha (ER alpha)/silent mating type information regulation 2 homolog 1 (SIRT1)-dependent antioxidant efficacy of 17 beta-estradiol against d-gal-induced oxidative damage-mediated cognitive dysfunction in a male mouse model. The results indicate that 17 beta-estradiol, by stimulating ER alpha/SIRT1, halts d-gal-induced oxidative stress-mediated JNK/NF-?B overexpression, neuroinflammation and neuronal apoptosis. Moreover, 17 beta-estradiol ameliorated d-gal-induced AD-like pathophysiology, synaptic dysfunction and memory impairment in adult mouse brains. Interestingly, inhibition of SIRT1 with Ex527 (a potent and selective SIRT1 inhibitor) further enhanced d-gal-induced toxicity and abolished the beneficial effect of 17 beta-estradiol. Most importantly, for the first time, our molecular docking study reveals that 17 beta-estradiol allosterically increases the expression of SIRT1 and abolishes the inhibitory potential of d-ga. In summary, we can conclude that 17 beta-estradiol, in an ER alpha/SIRT1-dependent manner, abrogates d-gal-induced oxidative stress-mediated memory impairment, neuroinflammation, and neurodegeneration in adult mice.