Metal complexing agents as therapies for Alzheimer's disease
Metal complexing agents as therapies for Alzheimer's disease
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DOI：
10.1016/s0197-4580(02)00120-3
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发表时间：
2002-11-01
影响因子：
4.2
通讯作者：
Bush, AI
中科院分区：
文献类型：
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作者：
Bush, AI
阿尔茨海默病（AD）药物开发的现代研究方法靶向大脑中的β-淀粉样蛋白（Abeta）积累。主要的方法试图阻止Abeta产生（分泌酶抑制剂）或清除Abeta（疫苗）。然而，现在有令人信服的证据表明，Abeta不会自发聚集，而是与过量的脑金属（铜，铁和锌）发生年龄依赖性反应，诱导蛋白质沉淀成富含金属的物质（斑块）。Abeta与Cu或Fe的异常结合诱导过氧化氢的产生，这可能介导AD中对脑的显著氧化损伤。我们已经开发了金属结合化合物，其抑制Abeta在体外产生过氧化氢，以及逆转肽在体外和人脑尸检标本中的聚集。最近，其中一种化合物氯碘羟喹（CQ; USP抗生素）口服给予携带淀粉样蛋白的转基因小鼠9周，并成功地显著抑制了Abeta的积累。基于这些结果，CQ正在临床试验中进行测试。(C)2002年爱思唯尔科技有限公司All rights reserved.
Modern research approaches into drug development for Alzheimer's disease (AD) target beta-amyloid (Abeta) accumulation in the brain. The main approaches attempt to prevent Abeta production (secretase inhibitors) or to clear Abeta (vaccine). However, there is now compelling evidence that Abeta does not spontaneously aggregate, but that there is an age-dependent reaction with excess brain metal (copper, iron and zinc), which induces the protein to precipitate into metal-enriched masses (plaques). The abnormal combination of Abeta with Cu or Fe induces the production of hydrogen peroxide, which may mediate the conspicuous oxidative damage to the brain in AD. We have developed metal-binding compounds that inhibit the in vitro generation of hydrogen peroxide by Abeta, as well as reverse the aggregation of the peptide in vitro and from human brain post-mortem specimens. Most recently, one of the compounds, clioquinol (CQ; a USP antibiotic) was given orally for 9 weeks to amyloid-bearing transgenic mice, and succeeded in markedly inhibiting Abeta accumulation. On the basis of these results, CQ is being tested in clinical trials. (C) 2002 Elsevier Science Inc. All rights reserved.