Clioquinol effects on tissue chelatable zinc in mice.
Recent evidence for the involvement of zinc in the formation of beta-amyloid plaques in the brain in Alzheimer's disease has led to the establishment of new therapeutic strategies for the degenerative disorder based on metal chelation. The present experiment was conducted on a membrane-permeable zinc chelator, clioquinol (CQ), that has shown potential in initial studies on a mouse model of Alzheimer's disease [1]. The degree of chelatable zinc in mice treated with CQ, delivered by two different routes, was measured using complementary protocols for identifying chelatable zinc: 6-methoxy-8-quinolyl- p-toluenesulfonamide (TSQ) histofluorescence, and selenite autometalography. Mice injected intraperitoneally with CQ showed a dramatic reduction in chelatable zinc in brain, testis, and pancreas. In contrast, mice given CQ orally showed no significant change in levels of chelatable zinc in these tissues. This suggests that CQ administered orally to patients with Alzheimer's disease should not significantly perturb chelatable zinc levels in key organs and may be used over long periods without adverse endocrinological and reproductive effects related to zinc deficiency. In contrast, CQ injected intraperitoneally may be used not only as a tool for investigating chelatable zinc pools but also in a clinical context. For example, injected CQ could be employed in situations requiring the rapid buffering of excessive chelatable zinc following ischemic episodes or brain trauma. Thus, our findings indicate that CQ has considerable potential as a versatile scientific and clinical tool used for selective modulation of zinc pools.
Nitzan
Yuval B
YB
Department of Morphology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Sekler
Israel
I
Frederickson
Christopher J
CJ
Coulter
Douglas A
DA
Balaji
Rengarajan V
RV
Liang
Shu-Ling
SL
Margulis
Ariel
A
Hershfinkel
Michal
M
Silverman
William F
WF
D000284:Administration, Oral; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D007464:Clioquinol / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D000891:Anti-Infective Agents, Local; D002614:Chelating Agents; D007464:Clioquinol; D015032:Zinc