Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers
Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers
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DOI：
10.1073/pnas.0505723102
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发表时间：
2006-01-17
影响因子：
11.1
通讯作者：
Lipton, SA
中科院分区：
文献类型：
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作者：
Satoh, T;Okamoto, SI;Lipton, SA
亲电神经突生长促进前列腺素（NEPP）化合物保护神经元免受氧化损伤。NEPPs的至少部分神经保护作用在于诱导血红素加氧酶-1（HO-1），其沿着其它11相酶，作为对抗氧化应激的防御系统。在这里，我们发现，通过使用荧光标记和免疫沉淀试验，NEPPs优先被神经元吸收，并以巯基依赖的方式与转录因子Nrf2的负调节因子Keap1结合。通过与Keap1结合，NEPPs阻止Keap1介导的Nrf2失活，从而增强Nrf2易位到培养的神经元细胞的细胞核中。反过来，Nrf2与HO-1启动子的抗氧化剂/亲电响应元件结合以诱导HO-1表达。与这一概念相一致，如果抗氧化剂响应元件突变，则HO-1报告构建体的NEPP诱导被阻止。我们表明，NEPPs在体外和体内脑缺血/再灌注损伤（中风）模型中均具有神经保护作用，免受谷氨酸相关兴奋性毒性的影响。我们的研究结果表明，NEPPs通过激活Keap1/Nrf2/HO-1通路防止兴奋性毒性。由于NEPPs优先在神经元中积累，它们可能提供一类神经保护化合物，不同于其他亲电化合物，如叔丁基对苯二酚，其激活星形胶质细胞中的抗氧化剂反应元件。因此，NEPPs代表了中风和神经退行性疾病的治疗方法。
Electrophilic neurite outgrowth-promoting prostaglandin (NEPP) compounds protect neurons from oxidative insults. At least part of the neuroprotective action of NEPPs lies in induction of hemeoxygenase-1 (HO-1), which, along with other phase 11 enzymes, serve as a defense system against oxidative stress. Here, we found that, by using fluorescent tags and immunoprecipitation assays, NEPPs are taken up preferentially into neurons and bind in a thiol-dependent manner to Keap1, a negative regulator of the transcription factor Nrf2. By binding to Keap1, NEPPs prevent Keap1-mediated inactivation of Nrf2 and, thus, enhance Nrf2 translocation into the nucleus of cultured neuronal cells. In turn, Nrf2 binds to antioxidant/electrophile-responsive elements of the HO-1 promoter to induce HO-1 expression. Consistent with this notion, NEPP induction of an HO-1 reporter construct is prevented if the antioxidant-responsive elements are mutated. We show that NEPPs are neuroprotective both in vitro from glutamate-related excitotoxicity and in vivo in a model of cerebral ischemia/reperfusion injury (stroke). Our results suggest that NEPPs prevent excitotoxicity by activating the Keap1/Nrf2/HO-1 pathway. Because NEPPs accumulate preferentially in neurons, they may provide a category of neuroprotective compounds, distinct from other electrophilic compounds such as tertbutylhydroquinone, which activates the antioxidant-responsive element in astrocytes. NEPPs thus represent a therapeutic approach for stroke and neurodegenerative disorders.