TY - JOUR
T1 - Clioquinol attenuates zinc-dependent β-cell death and the onset of insulitis and hyperglycemia associated with experimental type I diabetes in mice
AU - Priel, Tsvia
AU - Aricha-Tamir, Barak
AU - Sekler, Israel
N1 - Funding Information:
We thank Dr. Ze'ev Silverman for the help with the immunohistochemical analysis and the critical comments and discussions throughout this project, and Ms. Oshrat Cohen for the technical assistance. This work was supported by an ISF Grant 456/02.1 (to I.S.) and the ISF equipment Grant 456/02.2 (to I.S.).
PY - 2007/6/22
Y1 - 2007/6/22
N2 - Zinc in the pancreas is co-released with insulin from β-cells reaching concentrations similar to those found in the vicinity of glutamatergic synapses. In the brain, the role of zinc in excitotoxic brain damage is well established. In contrast, its role in islet destruction during diabetes is poorly understood. We have studied the efficacy of zinc homeostatic proteins and an intracellular zinc chelator, clioquinol, in conferring resistance against zinc toxicity in pancreatic islets. We further assessed the ability of clioquinol to protect the islets in an experimental model of type I diabetes. Our results indicate that endogenous mechanisms for lowering [Zn]i are deficient in the insulinoma cell line, MIN6, and that permeation of Zn2+ triggered cell death. Application of the low affinity, intracellular zinc chelator, clioquinol, reduced Zn2+-induced cell death by 80%. In addition, chelation of zinc ions by clioquinol in vivo prevented onset of multiple low dose streptozotocin-induced diabetes, and reduced the insulitis and hyperglycemia associated with this model. Furthermore, the glucose tolerance test (GTT) score of multiple low dose streptozotocin (MLD-STZ) mice pretreated with clioquinol was, statistically indistinguishable from that of untreated, control mice. Taken together, our results point to the potential utility of in vivo zinc chelation as a therapeutic strategy for treatment of idiopathic type I diabetes.
AB - Zinc in the pancreas is co-released with insulin from β-cells reaching concentrations similar to those found in the vicinity of glutamatergic synapses. In the brain, the role of zinc in excitotoxic brain damage is well established. In contrast, its role in islet destruction during diabetes is poorly understood. We have studied the efficacy of zinc homeostatic proteins and an intracellular zinc chelator, clioquinol, in conferring resistance against zinc toxicity in pancreatic islets. We further assessed the ability of clioquinol to protect the islets in an experimental model of type I diabetes. Our results indicate that endogenous mechanisms for lowering [Zn]i are deficient in the insulinoma cell line, MIN6, and that permeation of Zn2+ triggered cell death. Application of the low affinity, intracellular zinc chelator, clioquinol, reduced Zn2+-induced cell death by 80%. In addition, chelation of zinc ions by clioquinol in vivo prevented onset of multiple low dose streptozotocin-induced diabetes, and reduced the insulitis and hyperglycemia associated with this model. Furthermore, the glucose tolerance test (GTT) score of multiple low dose streptozotocin (MLD-STZ) mice pretreated with clioquinol was, statistically indistinguishable from that of untreated, control mice. Taken together, our results point to the potential utility of in vivo zinc chelation as a therapeutic strategy for treatment of idiopathic type I diabetes.
KW - Clioquinol
KW - Diabetes
KW - MLD-STZ
KW - Zinc chelation
KW - Zinc homeostasis
UR - http://www.scopus.com/inward/record.url?scp=34249097722&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2007.02.064
DO - 10.1016/j.ejphar.2007.02.064
M3 - Article
AN - SCOPUS:34249097722
SN - 0014-2999
VL - 565
SP - 232
EP - 239
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -