Stoichiometry and conditional stability constants of Cu(II) or Zn(II) clioquinol complexes; implications for Alzheimer's and Huntington's disease therapy
Stoichiometry and conditional stability constants of Cu(II) or Zn(II) clioquinol complexes; implications for Alzheimer's and Huntington's disease therapy
复制标题
DOI：
10.1016/j.neuro.2007.02.004
复制
发表时间：
2007-05-01
期刊：
影响因子：
3.4
通讯作者：
Huidobro-Toro, J. Pablo
中科院分区：
文献类型：
--
作者：
Ferrada, Evandro;Arancibia, Veronica;Huidobro-Toro, J. Pablo
用5-氯-7-碘-8-羟基喹啉（氯碘喹啉，CQ）治疗阿尔茨海默病的成功试验促使人们重新关注评估其治疗作用是否与神经毒性微量金属（如Cu（II）和Zn（II））的配位有关。我们现在报告CQ Cu（II）和Zn（II）络合物在含有Ca（II）和Mg（II）离子的生物缓冲液中测量的条件稳定常数（K-C '）。紫外-可见光谱和极谱法证明Cu（II）和Zn（II）CQ络合物的化学计量比为1：2;计算的K-C 's为：Cu（CQ）（2）1.2 × 10（10）M-2和Zn（CQ）（2）7.0 × 10（8）M-2; CQ对Cu（II）的亲和力比Zn（II）的亲和力高至少一个数量级。为了测试Cu（II）CQ络合物在脑中可能的功能相关性，我们通过金属诱导的P2 X（4）受体（一种主要的脑P2 X受体）的ATP门控电流的抑制来生物测定游离Cu（II）浓度。CQ浓度依赖性地减少Cu（II）抑制ATP门控电流。鉴于CQ对Zn（II）的稳定性常数与A β-淀粉样蛋白对Zn（II）的稳定性常数相似，并且即使在竞争离子存在下，CQ也可以与Cu（II）形成络合物的事实，本结果强调了脑中Cu（II）CQ络合物的形成可以通过减少游离Cu（II）浓度从而改变脑兴奋性来起作用，或有利于β-淀粉样蛋白斑或亨廷顿蛋白的降解，而不是通过CQ本身的特定作用。(c)2007年由Elsevier Inc.出版
Successful trials with 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ) for Alzheimer's disease treatment prompted renewed interest in assessing whether its therapeutic action is related to the coordination of neurotoxic trace metals, such as Cu(II) and Zn(II). We now report conditional stability constants (K-C ') for CQ Cu(II) and Zn(II) complexes measured in a biological buffer containing Ca(II) and Mg(II) ions. UV-vis spectroscopy and polarography evidenced a 1:2 stoichiometry of Cu(II) and Zn(II) CQ complexes; the K-C ',s calculated were: Cu(CQ)(2) 1.2 x 10(10), and Zn(CQ)(2) 7.0 x 10(8) M-2; the CQ affinity for Cu(II) is at least an order of magnitude higher than for Zn(II). To test the possible functional relevance of the Cu(II) CQ complexes in the brain, we bioassayed free Cu(II) concentration by the metal-induced inhibition of ATP-gated currents of the P2X(4) receptor, a predominant brain P2X receptor. CQ reduced concentration-dependently the Cu(II) inhibition of the ATP-gated currents. In view that the stability constant of CQ for Zn(II) is similar to that of A beta-amyloid for Zn(II), and the fact that CQ may form complexes with Cu(II), even in the presence of competing ions, the present results highlight that the formation of Cu(II) CQ complexes in the brain may act by diminishing free Cu(II) concentrations modifying thereby brain excitability, or favoring the degradation of beta-amyloid plaques or huntingtin, rather than through a specific effect of CQ itself. (c) 2007 Published by Elsevier Inc.