Clioquinol inhibits zinc-triggered caspase activation in the hippocampal CA1 region of a global ischemic gerbil model.
BACKGROUND
Excessive release of chelatable zinc from excitatory synaptic vesicles is involved in the pathogenesis of selective neuronal cell death following transient forebrain ischemia. The present study was designed to examine the neuroprotective effect of a membrane-permeable zinc chelator, clioquinol (CQ), in the CA1 region of the gerbil hippocampus after transient global ischemia.


RESULTS
The common carotid arteries were occluded bilaterally, and CQ (10 mg/kg, i.p.) was injected into gerbils once a day. The zinc chelating effect of CQ was examined with TSQ fluorescence and autometallography. Neuronal death, the expression levels of caspases and apoptosis inducing factor (AIF) were evaluated using TUNEL, in situ hybridization and Western blotting, respectively. We were able to show for the first time that CQ treatment attenuates the ischemia-induced zinc accumulation in the CA1 pyramidal neurons, accompanied by less neuronal loss in the CA1 field of the hippocampus after ischemia. Furthermore, the expression levels of caspase-3, -9, and AIF were significantly decreased in the hippocampus of CQ-treated gerbils.


CONCLUSIONS
The present study indicates that the neuroprotective effect of CQ is related to downregulation of zinc-triggered caspase activation in the hippocampal CA1 region of gerbils with global ischemia.
Wang
Tao
T
Key Laboratory of Medical Cell Biology of Ministry of Education of China, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Zheng
Wei
W
Xu
He
H
Zhou
Jia-Min
JM
Wang
Zhan-You
ZY
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005849:Gerbillinae; D017403:In Situ Hybridization; D008297:Male
D051033:Apoptosis Inducing Factor; D002614:Chelating Agents; D007464:Clioquinol; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases