Stoichiometry and conditional stability constants of Cu(II) or Zn(II) clioquinol complexes; implications for Alzheimer's and Huntington's disease therapy.
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) 1.2x10(10), and Zn(CQ)(2) 7.0x10(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 Abeta-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.
Ferrada
Evandro
E
Centro de Regulación Celular y Patología, Prof. J.V. Luco e Instituto Milenio de Biología Fundamental y Aplicada, MIFAB, Departamento Fisiología, Facultad de Ciencias Biológicas y, Santiago, Chile. eaferrad@puc.cl
Arancibia
Verónica
V
Loeb
Bárbara
B
Norambuena
Ester
E
Olea-Azar
Claudio
C
Huidobro-Toro
J Pablo
JP
D000255:Adenosine Triphosphate / Q000502:physiology; D000465:Algorithms; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D007464:Clioquinol / Q000737:chemistry* / Q000627:therapeutic use*; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy*; D015640:Ion Channel Gating / Q000187:drug effects; D008845:Microinjections; D009865:Oocytes / Q000502:physiology; D011048:Polarography; D018048:Receptors, Purinergic P2 / Q000235:genetics; D058848:Receptors, Purinergic P2X4; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D014982:Xenopus laevis; D015032:Zinc / Q000737:chemistry*
C548226:P2RX4 protein, human; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D012996:Solutions; D003300:Copper; D007464:Clioquinol; D000255:Adenosine Triphosphate; D015032:Zinc