A novel approach to screening for new neuroprotective compounds for the treatment of stroke
A novel approach to screening for new neuroprotective compounds for the treatment of stroke
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DOI：
10.1016/j.brainres.2007.07.061
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发表时间：
2007-10-10
期刊：
影响因子：
2.9
通讯作者：
Lapchak, Paul A.
中科院分区：
文献类型：
--
作者：
Maher, Pamela;Salgado, Karmen F.;Lapchak, Paul A.
尽管在细胞和分子水平上对脑缺血的病理生理学的理解已经取得了重大进展，但只有一种药物，即溶血栓组织纤溶酶原激活剂（rt-PA），被FDA批准用于急性缺血性卒中患者。因此，迫切需要额外的安全有效的中风治疗方法。为了鉴定可能有效的新型化合物，我们开发了一种以死亡为终点的基于细胞培养的测定法作为筛选工具。我们已经进行了初步筛选潜在的神经保护药物之间的一组黄酮类化合物，通过使用小鼠海马细胞系，HT 22，结合化学缺血。进一步筛选提供了ATP和谷胱甘肽，主要的细胞内抗氧化剂，以及长期诱导的抗氧化蛋白的生化测定。根据这些筛选的结果，我们在兔脑缺血的小血栓栓塞模型中测试了最好的黄酮类化合物非瑟酮。非瑟酮显着减少了中风后的行为缺陷，为这种新方法提供了原则证据，以确定治疗中风的新化合物。(C)2007 Elsevier B. V.保留所有权利。
Despite the significant advances that have been made in understanding the pathophysiology of cerebral ischemia on the cellular and molecular level, only one drug, the thrombolytic tissue plasminogen activator (rt-PA), is approved by the FDA for use in patients with acute ischemic stroke. Therefore, there is a critical need for additional safe and effective treatments for stroke. In order to identify novel compounds that might be effective, we have developed a cell culture-based assay with death being an endpoint as a screening tool. We have performed an initial screening for potential neuroprotective drugs among a group of flavonoids by using the mouse hippocampal cell line, HT22, in combination with chemical ischemia. Further screens were provided by biochemical assays for ATP and glutathione, the major intracellular antioxidant, as well as for long-term induction of antioxidant proteins. Based upon the results of these screens, we tested the best flavonoid, fisetin, in the small clot embolism model of cerebral ischemia in rabbits. Fisetin significantly reduced the behavioral deficits following a stroke, providing proof of principle for this novel approach to identifying new compounds for the treatment of stroke. (C) 2007 Elsevier B.V. All rights reserved.