Yamauchi Keita, Nakano Yusuke, Imai Takahiko, Takagi Toshinori, Tsuruma Kazuhiro, Shimazawa Masamitsu, Iwama Toru, Hara Hideaki
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan; Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
Neuroscience. 2016 Oct 1;333:302-10. doi: 10.1016/j.neuroscience.2016.07.035. Epub 2016 Jul 27.
Recanalization of occluded vessels leads to ischemia-reperfusion injury (IRI), with oxidative stress as one of the main causes of injury, despite the fact that recanalization therapy is the most effective treatment for ischemic stroke. The nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the transcription factors which has an essential role in protection against oxidative stress. RS9 is a novel Nrf2 activator obtained from bardoxolone methyl (BARD), an Nrf2 activator that has already been tested in a clinical trial, using a biotransformation technique. RS9 has been reported to lead to higher Nrf2 activation and less cytotoxicity than BARD. In this study, we investigated the effects of RS9 on IRI. Mice were intraperitoneally treated immediately after 2h of transient middle cerebral artery occlusion (MCAO) with a vehicle solution or 0.2mg/kg of RS9. Post-onset treatment of RS9 attenuated the infarct volume and improved neurological deficits 22h after reperfusion. RS9 activated Nrf2 2 and 6h after reperfusion and activated heme oxygenase-1 at 6 and 22h after reperfusion. RS9 also attenuated the phosphorylation of NF-κB p65 2 and 6h after reperfusion. Finally, RS9 improved the survival rate and neurological deficits 7days after MCAO. Our results suggest that the activation of Nrf2 by RS9 has a neuroprotective effect, mediated by attenuating both oxidative stress and neuroinflammation, and that RS9 is an effective therapeutic candidate for the treatment of IRI.
尽管再通治疗是缺血性中风最有效的治疗方法，但闭塞血管的再通会导致缺血再灌注损伤（IRI），氧化应激是损伤的主要原因之一。核因子红细胞2相关因子2（Nrf2）是一种转录因子，在抵抗氧化应激中起重要作用。RS9是一种新型Nrf2激活剂，它是通过生物转化技术从已在临床试验中进行测试的Nrf2激活剂巴多昔芬甲基（BARD）中获得的。据报道，RS9比BARD能导致更高的Nrf2激活和更低的细胞毒性。在本研究中，我们研究了RS9对IRI的影响。在短暂性大脑中动脉闭塞（MCAO）2小时后，立即给小鼠腹腔注射溶媒溶液或0.2mg/kg的RS9。再灌注后22小时，RS9的发病后治疗减轻了梗死体积并改善了神经功能缺损。再灌注后2小时和6小时，RS9激活了Nrf2，再灌注后6小时和22小时，RS9激活了血红素加氧酶-1。再灌注后2小时和6小时RS9还减弱了NF-κB p65的磷酸化。最后，RS9提高了MCAO后7天的存活率并改善了神经功能缺损。我们的结果表明，RS9激活Nrf2具有神经保护作用，其机制是减轻氧化应激和神经炎症，并且RS9是治疗IRI的有效候选药物。
