The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice
The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice
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DOI：
10.1038/aps.2010.101
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发表时间：
2010-11-01
影响因子：
8.2
通讯作者：
Zhang, Jian-min
中科院分区：
文献类型：
--
作者：
Hong, Yuan;Yan, Wei;Zhang, Jian-min
目的：为了确定Nrf 2信号通路激活是否可以减轻创伤性脑损伤（TBI）后的氧化应激和神经元损伤。方法：在Sprague-Dawley大鼠和Nrf 2基因敲除或对照小鼠中进行控制性皮质撞击（CCI）损伤。萝卜硫素（SFN）是一种有效的Nrf 2激活剂，用于激活Nrf 2。氧化应激，病变体积，神经元变性，神经功能障碍，采用生物化学，组织病理学和神经行为学的方法进行了测定。采用Western印迹分析和RT-PCR评估Nrf 2和抗氧化酶血红素加氧酶1（HO-1）和NAD（P）H：奎宁氧化还原酶1（NQO 1）的蛋白和mRNA水平。通过SFN激活Nrf 2（5 mg/kg，ip）诱导核转位和Nrf 2活化，这导致TBI后Nrf 2依赖性抗氧化酶的上调和氧化损伤的减少。根据这些生化变化，SFN也显着减少TBI后神经元死亡，挫伤体积和神经功能障碍。此外，Nrf 2基因敲除小鼠TBI后表现出更严重的氧化应激和神经功能缺损，并没有受益于SFN的影响。结论：Nrf 2在细胞防御TBI的氧化应激中起着关键作用。此外，通过小分子诱导剂如SFN对Nrf 2信号传导途径的药理学激活减弱了TBI后的氧化应激和神经元损伤。
Aim: To determine whether Nrf2 signaling pathway activation could attenuate oxidative stress and neuronal damage following traumatic brain injury (TBI).Methods: Controlled cortical impact (CCI) injury was performed in Sprague-Dawley rats and Nrf2-knockout or control mice. Sulforaphane (SFN), a potent Nrf2 activator, was used to activate Nrf2. Oxidative stress, lesion volume, neuron degeneration, and neurologic dysfunction were determined using biochemical, histopathological and neuroethologic approaches. Protein and mRNA levels of Nrf2 and the antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P) H: quinine oxidoreductase 1 (NQO1) were assessed using Western blot analysis and RT-PCR.Results: Activation of Nrf2 by SFN(5 mg/kg, ip) induced the nuclear translocation and activation of Nrf2, which resulted in an up-regulation of Nrf2-dependent antioxidant enzymes and a reduction of oxidative damage after TBI. In accordance with these biochemical changes, SFN also significantly reduced neuronal death, contusion volume, and neurological dysfunction after TBI. Furthermore, Nrf2-knockout mice showed more severe oxidative stress and neurologic deficits after TBI and did not benefit from the effects of SFN.Conclusion: Nrf2 plays a pivotal role in cell defenses against the oxidative stress of TBI. In addition, pharmacological activation of the Nrf2 signaling pathway by small molecule inducers such as SFN attenuated oxidative stress and neuronal damage following TBI.