There is an urgent need to develop effective therapies for ischemic stroke, but the complicated pathological processes after ischemia make doing so difficult. In the current study, we identified a novel diaryl acylhydrazone derivative, A11, which has multiple neuroprotective properties in ischemic stroke models. First, A11 was demonstrated to induce neuroprotection against ischemic injury in a dose-dependent manner (from 0.3 to 3 μM) in three in vitro experimental ischemic stroke models: oxygen glucose deprivation (OGD), hydrogen peroxide, and glutamate-stimulated neuronal cell injury models. Moreover, A11 was able to potently alleviate three critical pathological changes, apoptosis, oxidative stress, and mitochondrial dysfunction, following ischemic insult in neuronal cells. Further analysis revealed that A11 upregulated the phosphorylation levels of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in OGD-exposed neuronal cells, suggesting joint activation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MEK)/ERK pathways. In rats with middle cerebral artery occlusion, single-dose administration of A11 (3 mg/kg per day, i.v.) at the onset of reperfusion significantly reduced the infarct volumes and ameliorated neurological deficits. Our study, for the first time, reports the anti-ischemic effect of diaryl acylhydrazone chemical entities, especially A11, which acts on multiple ischemia-associated pathological processes. Our results may provide new clues for the development of an effective therapeutic agent for ischemic stroke.

中文翻译：

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A11是一种新型的二芳基酰基hydr衍生物，可在体内和体外发挥抗缺血性损伤的神经保护作用。

迫切需要为缺血性中风开发有效的治疗方法，但是缺血后复杂的病理过程使其变得如此困难。在当前的研究中，我们确定了一种新型的二芳基酰基hydr衍生物A11，在缺血性中风模型中具有多种神经保护特性。首先，在三种体外实验性缺血性中风模型：氧葡萄糖剥夺（OGD），过氧化氢和谷氨酸刺激的神经元细胞损伤的三种体外实验中，A11被证明以剂量依赖性方式（0.3至3μM）诱导神经保护作用。楷模。此外，在缺血性损伤神经元细胞后，A11能够有效缓解三种关键的病理变化，即细胞凋亡，氧化应激和线粒体功能障碍。进一步的分析表明，A11上调了OGD暴露的神经元细胞中蛋白激酶B（AKT）和细胞外信号调节激酶（ERK）的磷酸化水平，表明磷酸肌醇3-激酶（PI3K）/ AKT和有丝分裂原激活的联合活化蛋白激酶（MEK）/ ERK途径。在患有大脑中动脉闭塞的大鼠中，在再灌注开始时单剂量给予A11（每天3 mg / kg，静脉注射）可显着减少梗塞体积并改善神经功能缺损。我们的研究首次报道了二芳基酰基hydr化学实体（尤其是A11）的抗缺血作用，该化学实体作用于多个与缺血相关的病理过程。我们的结果可能为开发有效的缺血性卒中治疗剂提供新的线索。