Shih Andy Y, Li Ping, Murphy Timothy H
Department of Psychiatry, Kinsmen Laboratory of Neurological Research and Brain Research Center, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
J Neurosci. 2005 Nov 2;25(44):10321-35. doi: 10.1523/JNEUROSCI.4014-05.2005.
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.
转录因子核因子红细胞2相关因子2（Nrf2）可协调自由基清除、外源性物质解毒及氧化还原电位维持所需基因的表达。此前，在模拟中风损伤部分成分的细胞培养模型中，这种多效性反应的激活具有神经保护作用。然而，Nrf2在限制体内中风损伤中的作用仍不清楚。我们报告称，Nrf2激活可在体内保护大脑免受脑缺血损伤。用叔丁基对苯二酚（tBHQ，一种Nrf2活性诱导剂）对大鼠进行急性（1 - 3天）脑室内或腹腔预处理，可减轻缺血再灌注后24小时甚至1个月时的皮质损伤和感觉运动功能障碍。给大鼠和表达Nrf2的小鼠注射tBHQ后，皮质谷胱甘肽水平显著升高，但Nrf2基因敲除小鼠未出现此现象。与Nrf2野生型对照相比，Nrf2基因敲除小鼠中抗氧化/解毒酶的基础活性和诱导活性均降低。有趣的是，在中风后7天，Nrf2基因敲除小鼠出现更大的梗死灶，但在24小时时未出现，这表明Nrf2可能在缺血发作后很长时间内对半暗带的形成起作用。通过脑室内注射内皮素 - 1建立的“半暗带”中风模型导致的神经元死亡，在给Nrf2野生型小鼠注射tBHQ后得到减轻，但Nrf2基因敲除小鼠未出现此现象，这证实了tBHQ在体内对Nrf2的特异性作用。我们得出结论，Nrf2在调节体内缺血性损伤中发挥作用。因此，小分子诱导剂激活Nrf2可能是对易患中风患者的一种切实可行的预防性治疗方法。
