Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke.
Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke.
复制标题
含有四甲基吡嗪和肉碱亚结构的新型孪生化合物在实验性缺血性中风中的治疗潜力
DOI：
10.1155/2017/7191856
复制
发表时间：
2017
影响因子：
--
通讯作者：
Yi F
中科院分区：
文献类型：
--
作者：
Wang Z;Zhou Z;Wei X;Wang M;Wang BO;Zhang Y;He X;Sun Y;Wang X;Sun M;Zhang Y;Gong X;Yi F
尽管研究在氧化应激、炎症、兴奋性毒性、钙超载和细胞凋亡等中风发病机制的理解方面取得了巨大进展，但中风治疗的实施仍然是一个巨大的挑战。本研究设计并合成了一系列新型的含川芎嗪和肉毒碱亚结构的孪生化合物，并探讨其对脑卒中相关神经元损伤的治疗潜力和作用机制。我们首先筛选了候选化合物的神经保护作用，发现在测试的化合物中，LR 134和LR 143表现出显著的神经保护作用，如通过减少脑缺血/再灌注损伤后大鼠的脑梗死和水肿、改善神经功能以及血脑屏障完整性所证明的。我们进一步证明了化合物LR 134和LR 143的神经保护作用与减少炎症反应和NADPH氧化酶-（NOX 2-）介导的氧化应激以及保护线粒体伴随着能量供应的改善有关。总之，这项研究提供了直接证据，表明含有川芎嗪和肉毒碱亚结构的新型双胞胎化合物具有多个治疗靶点的神经保护作用，表明这些化学结构的调节可能是治疗中风患者的创新治疗策略。
Although studies have seen dramatic advances in the understanding of the pathogenesis of stroke such as oxidative stress, inflammation, excitotoxicity, calcium overload and apoptosis, the delivery of stroke therapies is still a great challenge. In this study, we designed and synthesized a series of novel twin compounds containing tetramethylpyrazine and carnitine substructures and explored their therapeutic potential and mechanism in stroke-related neuronal injury. We first screened the neuroprotective effects of candidate compounds and found that among the tested compounds, LR134 and LR143 exhibited significant neuroprotection as evidenced by reducing cerebral infarct and edema, improving neurological function as well as blood-brain barrier integrity in rats after cerebral ischemia/reperfusion injury. We further demonstrated that the neuroprotective effects of compounds LR134 and LR143 were associated with the reduced inflammatory responses and NADPH oxidase- (NOX2-) mediated oxidative stress and the protection of mitochondria accompanied by the improvement of energy supply. In summary, this study provides direct evidence showing that the novel twin compounds containing tetramethylpyrazine and carnitine substructures have neuroprotective effects with multiple therapeutic targets, suggesting that modulation of these chemical structures may be an innovative therapeutic strategy for treating patients with stroke.
登录
查看更多内容
影响因子：
37.8
作者：
Fan LM;Douglas G;Bendall JK;McNeill E;Crabtree MJ;Hale AB;Mai A;Li JM;McAteer MA;Schneider JE;Choudhury RP;Channon KM
通讯作者：
Channon KM
影响因子：
8.3
作者：
Vosler PS;Graham SH;Wechsler LR;Chen J
通讯作者：
Chen J
影响因子：
5.3
作者：
Folbergrová J;Ješina P;Kubová H;Druga R;Otáhal J
通讯作者：
Otáhal J
影响因子：
3.7
作者：
Li L;Tan H;Gu Z;Liu Z;Geng Y;Liu Y;Tong H;Tang Y;Qiu J;Su L
通讯作者：
Su L
影响因子：
5.1
作者：
Sanderson, Thomas H.;Reynolds, Christian A.;Kumar, Rita;Przyklenk, Karin;Huettemann, Maik
通讯作者：
Huettemann, Maik