Neuronal sensitivity to kainic acid is dependent on the Nrf2-mediated actions of the antioxidant response element
Neuronal sensitivity to kainic acid is dependent on the Nrf2-mediated actions of the antioxidant response element
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DOI：
10.1111/j.1471-4159.2006.04019.x
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Johnson, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Kraft, Andrew D.;Lee, Jong-Min;Johnson, Jeffrey A.
转录因子，核因子E2（红细胞衍生2）相关因子2（Nrf2），是必不可少的诱导电池的第二阶段解毒基因通过抗氧化反应元件（ARE），位于其启动子区域。由ARE驱动的基因响应于细胞环境的各种应激源而上调。细胞还原电位的这些遗传变化可能反映了对有害毒物的内在损伤反应。红藻氨酸注射后的转基因报告小鼠的分析显示，在受损的海马内选择性ARE激活。此外，2 × 2微阵列分析比较Nrf2基因敲除与野生型campi揭示了与离子运动和髓鞘形成相关的基因变化，除了改变解毒相关的基因。Nrf2基因敲除小鼠对红藻氨酸毒性更敏感，表现为癫痫发作严重程度、癫痫发作持续时间、海马神经元损伤和死亡率升高。注射红藻氨酸的敲除小鼠显示改变的胶质细胞酸性蛋白免疫反应性和增加的小胶质细胞浸润。野生型敲除损伤差异不依赖于兴奋性毒素的外周代谢，与癫痫发作易感性增加密切相关，因此不一定是Nrf2的神经保护作用。这些结果联合收割机支持Nrf2在成人大脑神经细胞防御反应中的作用。
The transcription factor, nuclear factor E2 (erythroid-derived 2)-related factor 2 (Nrf2), is essential for the induction of a battery of phase II detoxification genes through the antioxidant response element (ARE) that lies in their promoter region. Genes driven by the ARE are up-regulated in response to various stressors of the cellular environment. These genetic changes to the cellular reducing potential may reflect an intrinsic damage response to harmful toxicants. Analysis of transgenic reporter mice following kainate injection revealed selective ARE activation within the damaged hippocampus. Further, 2 x 2 microarray analyses comparing Nrf2 knockout versus wild-type hippocampi unmasked gene changes associated with ion movement and myelination, in addition to alterations to detoxification-related genes. Nrf2 knockout mice were more sensitive to kainate toxicity, as evidenced by elevated seizure severity, seizure duration, hippocampal neuron damage and mortality. Knockout mice injected with kainate displayed altered glial fibrillary acidic protein immunoreactivity and increased microglial infiltration. The wild-type to knockout damage differential was not dependent on the peripheral metabolism of the excitotoxin, was well correlated with increased seizure susceptibility, and was therefore not necessarily the neuroprotective effects of Nrf2. These results combine to support a role for Nrf2 in the neural cell defense response of the adult brain.