Abstract：
Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α\' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α\' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α\'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS.
摘要：
缺血性脑卒中是严重威胁人类健康的疾病。天然衍生的小分子（E）-5-（2-（喹啉-4-基）乙烯基）苯-1,3-二醇（RV01）是白藜芦醇的喹啉基类似物，在治疗IS方面具有巨大潜力。这项研究的目的是研究RV01对IS的保护作用的潜在机制和靶标。采用小鼠大脑中动脉阻塞再灌注（MCAO/R）和氧糖剥夺再灌注（OGD/R）模型来评估RV01对缺血性损伤和神经保护的影响。发现RV01显着增加SH-SY5Y细胞的存活率并防止OGD/R诱导的SH-SY5Y细胞凋亡。此外，RV01通过促进OGD/R暴露的SH-SY5Y细胞的线粒体自噬来减轻氧化应激和线粒体损伤。CK2α的敲低消除了RV01介导的促进线粒体自噬和减轻OGD/R后线粒体损伤以及神经元损伤。分子对接进一步证实了这些结果,药物亲和响应靶标稳定性和细胞热转移测定分析。重要的是,体内研究表明，用CK2α抑制剂CX-4945治疗消除了RV01介导的脑梗死体积的缓解，脑水肿,MCAO/R小鼠的脑血流量和神经功能缺损。这些数据表明，RV01通过与CK2α相互作用促进线粒体自噬，从而有效减少急性缺血性卒中引起的损伤。这些发现为RV01对IS发挥治疗作用的潜在机制提供了有价值的见解。
