Molecular shuttle chelation: The use of ascorbate, desferrioxamine and Feralex-G in combination to remove nuclear bound aluminum
Molecular shuttle chelation: The use of ascorbate, desferrioxamine and Feralex-G in combination to remove nuclear bound aluminum
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DOI：
10.1023/b:cemn.0000022773.70722.b2
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发表时间：
2004-06-01
影响因子：
4
通讯作者：
Lukiw, WJ
中科院分区：
文献类型：
--
作者：
Kruck, TP;Cui, JG;Lukiw, WJ
1.大量数据表明，铝(Al(III))暴露可能是导致包括阿尔茨海默病(AD)在内的几种人类神经退行性疾病的发展、进展和/或神经病理的环境风险因素。核似乎是Al(III)结合、积累和Al(III)介导的功能障碍的一个直接靶点，部分原因是它们含有高含量的多磷酸化核酸、核苷酸和核蛋白。因此，设计从这些遗传间隔中去除Al(III)的螯合疗法是一种有吸引力的策略，可以缓解因过量暴露Al(III)而可能导致的中枢神经系统功能障碍的发展和/或进展。在这项研究中，我们研究了10种天然和合成的铝(III)螯合剂的潜在应用，包括抗坏血酸(AS)、去铁胺(DF)和Feralex-G(FG)，它们单独或联合使用，以去除预先与完整的人脑细胞核孵育的Al(III)。虽然核结合的Al(III)被发现很难去除，但AS+FG的组合被发现在从核基质中去除Al(III)特别有效。我们的数据表明，带有顺式羟基酮基团的螯合剂，如FG，特别适合于从复杂的生物体系中去除Al(III)。我们进一步提出了一种机制，即小的螯合分子可以穿透原子核，结合Al(III)，扩散到较大的DF或FG分子可访问的区域，并将它们的Al(III)转移到DF或FG.8。这种被称为分子穿梭络合的机制可能为铝(III)超负荷疾病的潜在治疗提供一种有用的药物疗法。
1. Abundant data suggest that aluminum (Al(III)) exposure may be an environmental risk factor contributing to the development, progression and/or neuropathology of several human neurodegenerative disorders, including Alzheimer's disease (AD).2. Nuclei appear to be one directed target for Al(III) binding, accumulation, and Al(III)-mediated dysfunction due in part to their high content of polyphosphorylated nucleic acids, nucleotides, and nucleoproteins.3. The design of chelation therapies dealing with the removal of Al(III) from these genetic compartments therefore represents an attractive strategy to alleviate the development and/or progression of central nervous system dysfunction that may arise from excessive Al(III) exposure.4. In this study we have investigated the potential application of 10 natural and synthetic Al(III) chelators, including ascorbate (AS), desferrioxamine (DF), and Feralex-G (FG), used either alone or in combination, to remove Al(III) preincubated with intact human brain cell nuclei.5. Although nuclear bound Al( III) was found to be highly refractory to removal, the combination of AS+FG was found to be particularly effective in removing Al(III) from the nuclear matrix.6. Our data suggest that chelators carrying cis-hydroxy ketone groups, such as FG, are particularly suited to the removal of Al( III) from complex biological systems.7. We further suggest a mechanism whereby small chelating molecules may penetrate the nucleus, bind Al( III), diffuse to regions accessible by the larger DF or FG molecules and transfer their Al( III) to DF or FG.8. The proposed mechanism, called molecular shuttle chelation may provide a useful pharmacotherapy in the potential treatment of Al(III) overload disease.