Clioquinol and other hydroxyquinoline derivatives inhibit Abeta(1-42) oligomer assembly.
Clioquinol and other hydroxyquinoline derivatives inhibit Abeta(1-42) oligomer assembly.
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DOI：
10.1016/j.neulet.2009.08.002
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发表时间：
2009-11-06
影响因子：
2.5
通讯作者：
Augelli-Szafran CE
中科院分区：
文献类型：
--
作者：
LeVine H 3rd;Ding Q;Walker JA;Voss RS;Augelli-Szafran CE
可溶性低聚淀粉样蛋白-β (a β)对许多细胞类型都有毒性，是阿尔茨海默病的一个假定的病因。通过单位点生物素化a β(1-42)寡聚物组装试验，对nads - custom收集的1040种药物和生物活性化合物进行了机器人筛选，以抑制a β寡聚物的形成。几种喹啉类化合物的IC50值< 10 μM，其中包括对金属离子代谢有影响的抗原虫氯喹啉。在100 μM浓度下，2-OH、4-OH和6-OH喹啉不能阻断a β低聚物的形成。氯喹诺类似物在Aβ病理小鼠模型中显示出降低Aβ水平和改善行为缺陷的活性。氯喹诺和其他8-OH喹啉衍生物对体外低聚物形成的抑制作用与它们的螯合活性无关。交联研究表明，氯喹诺在三聚体形成阶段起作用。这些初步数据可能表明，8-羟基喹啉具有抑制Aβ低聚物形成的潜力，在动物模型和临床试验中评估这些化合物的作用时应考虑到这一点。
Soluble oligomeric amyloid-β (Aβ) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active compounds was robotically screened for inhibitors of Aβ oligomer formation with a single-site biotinylated Aβ(1-42) oligomer assembly assay. Several quinoline-like compounds were identified with IC50's < 10 μM, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism. The 2-OH, 4-OH, and 6-OH quinolines do not block Aβ oligomer formation up to a concentration of 100 μM. Analogs of clioquinol have shown activity in reducing Aβ levels and improving behavioral deficits in mouse models of Aβ pathology. The inhibitory effects of clioquinol and other 8-OH quinoline derivatives on oligomer formation in vitro are unrelated to their chelating activity. Crosslinking studies suggest that clioquinol acts at the stage of trimer formation. These preliminary data may suggest that 8-OH quinolines have the potential for suppressing Aβ oligomer formation which should be considered when assessing the effects of these compounds in animal models and clinical trials.
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影响因子：
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作者：
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