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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo.
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A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo.

机译:小分子诱导的Nrf2介导的抗氧化剂反应可有效预防体内脑缺血。

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摘要

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Previously, activation of this pleiotropic response was neuroprotective in cell culture models that simulate components of stroke damage. However, the role of Nrf2 in limiting stroke damage in vivo remained unclear. We report that Nrf2 activation protects the brain from cerebral ischemia in vivo. Acute (1-3 d) intracerebroventricular or intraperitoneal pretreatment with tert-butylhydroquinone (tBHQ), an Nrf2 activity inducer, reduced cortical damage and sensorimotor deficit at 24 h and even 1 month after ischemia-reperfusion in rats. Cortical glutathione levels robustly increased with tBHQ administration to rats and Nrf2-expressing mice, but not Nrf2(-/-) mice. Basal and inducible activities of antioxidant/detoxification enzymes in Nrf2(-/-) mice were reduced when compared with Nrf2(+/+) controls. Interestingly, larger infarcts were observed in Nrf2(-/-) mice at 7 d after stroke, but not at 24 h, suggesting that Nrf2 may play a role in shaping the penumbra well after the onset of ischemia. Neuronal death caused by a "penumbral" model of stroke, using intracortical endothelin-1 microinjection, was attenuated by tBHQ administration to Nrf2(+/+), but not to Nrf2(-/-) mice, confirming the Nrf2-specific action of tBHQ in vivo. We conclude that Nrf2 plays a role in modulating ischemic injury in vivo. Accordingly, Nrf2 activation by small molecule inducers may be a practical preventative treatment for stroke-prone patients.
机译:转录因子核因子红系2相关因子2(Nrf2)协调自由基清除,异物解毒和维持氧化还原电位所需的基因表达。以前,在模拟中风损害成分的细胞培养模型中,这种多效反应的激活具有神经保护作用。但是,Nrf2在限制体内中风损害中的作用尚不清楚。我们报告说,Nrf2激活保护大脑免受体内脑缺血。用Ntf2活性诱导剂叔丁基对苯二酚(tBHQ)进行急性(1-3 d)脑室内或腹膜内预处理,可在大鼠缺血再灌注后24小时甚至1个月减少皮质损伤和感觉运动功能障碍。皮质谷胱甘肽水平随着向大鼠和表达Nrf2的小鼠(而非Nrf2(-/-)小鼠)施用tBHQ而强劲增加。与Nrf2(+ / +)对照相比,Nrf2(-/-)小鼠中抗氧化剂/解毒酶的基础活性和诱导活性降低。有趣的是,Nrf2(-/-)小鼠在中风后7 d观察到更大的梗塞,但在24 h时未见梗塞,这表明Nrf2可能在缺血发作后很好地塑造半影。通过向Nrf2(+ / +)施用tBHQ,而非使用Nrf2(-/-)小鼠,减轻了使用皮层内内皮素1微量注射的“半影”中风模型引起的神经元死亡,证实了Nrf2的特定作用体内tBHQ。我们得出结论,Nrf2在体内调节缺血性损伤中起作用。因此,对于易中风的患者,小分子诱导剂激活Nrf2可能是一种实用的预防方法。

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