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The immunophilin‐ligands FK506 and V‐10,367 mediate neuroprotection by the heat shock response
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The immunophilin‐ligands FK506 and V‐10,367 mediate neuroprotection by the heat shock response
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Journal Article
The immunophilin‐ligands FK506 and V‐10,367 mediate neuroprotection by the heat shock response
2003
Overview
The macrolid FK506 is widely used in transplantation to suppress allograft rejection. FK506 and its derivatives are powerful neuroprotective molecules, but the underlying mechanisms remain to be resolved. We have previously shown that the FK506 mediated neuroprotection against oxygen radicals is independent of the inhibition of calcineurin but depends on de novo protein synthesis. Here, we have shown that FK506 mediates protection against H2O2, UV‐light or thapsigargin in neuronal cell lines, but not in non‐neuronal cells such as R3T3 fibroblasts. We compared in detail the effect of FK506 on apoptotic features in PC12 cells after H2O2 with V‐10,367 which binds to FKBPs but does not inhibit calcineurin. Both molecules exert the same neuroprotective effect after H2O2 stimulation. FK506, but not V‐10,367, inhibited the cytochrome c release out of the mitochondria and the caspase 3 activation, while both molecules inhibited the cleavage of Poly‐(ADP‐ribose)‐polymerase (Parp) and prevented the expression of p53. FK506 and V‐10,367 rapidly induced the expression of Hsp70 and Hsp27, but not Hsp90. Their neuroprotective actions could be completely blocked by quercetin, a functional inhibitor of the heat shock proteins. We conclude that immunophilin‐ligands such as FK506 and V‐10,367 exert their neuroprotection independent of calcineurin through the induction of the heat shock response. The identification of the underlying signal transduction from application of immunophilin ligands to the expression of heat shock proteins represents a novel target cascade for neuroprotection. British Journal of Pharmacology (2003) 138, 1004–1012. doi:10.1038/sj.bjp.0705132
Publisher
Blackwell Publishing Ltd,Nature Publishing
Subject
/ Biological and medical sciences
/ Cell Survival - drug effects
/ Dose-Response Relationship, Drug
/ FK506
/ Heat-Shock Proteins - agonists
/ Heat-Shock Proteins - biosynthesis
/ Heat-Shock Response - drug effects
/ Heat-Shock Response - physiology
/ Immunophilins - pharmacology
/ Ligands
/ Neuroprotective Agents - metabolism
/ Neuroprotective Agents - pharmacology
/ p53
/ Poly‐(ADP‐ribose)‐polymerase
/ Rats
/ V‐10,367
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