Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform
Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform
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DOI：
10.1073/pnas.0600930103
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发表时间：
2006-07-05
影响因子：
11.1
通讯作者：
Lo, Donald C.
中科院分区：
文献类型：
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作者：
Wang, James K. T.;Portbury, Stuart;Lo, Donald C.
我们在这里报告的结果，化学遗传筛选使用已知的药理学小分子加上大脑皮层切片为基础的缺血性中风模型。我们鉴定了一种小分子化合物，其在缺血性中风中以前未被认识到具有神经保护作用，强心苷Neriifolin，并证明其在脑切片测定中的性质包括超过6小时的延迟治疗潜力。Neriifolin在结构上与洋地黄类强心苷相关，其推定的靶点是Na+/K+-ATP酶。测试的其他强心苷化合物也显示出神经保护活性，尽管具有较低的表观效力。在随后的整体动物研究中，我们发现，Neriifolin提供了显着的神经保护在缺氧/缺血的新生儿模型和大脑中动脉闭塞模型的短暂局灶性缺血。Na+/K+-ATP酶的神经保护潜力特别令人感兴趣，因为它具有已知的“可药用性”;事实上，食品和药物管理局批准的小分子化合物如洋地黄毒苷和地高辛已在临床上用于充血性心力衰竭和心律失常数十年。因此，现有的强心苷或密切相关的化合物可以为缺血性卒中的临床试验测试提供加速途径。我们的研究结果强调了假设中立，高含量，基于组织的筛选在识别新的候选药物和药物靶点方面可以发挥重要作用，用于治疗目前尚未获得有效治疗途径的疾病。
We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na+/K+-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na+/K+-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.