The immunophilin-ligands FK506 and V-10,367 mediate neuroprotection by the heat shock response.
(1) 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. (2) Here, we have shown that FK506 mediates protection against H(2)O(2), 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 H(2)O(2) with V-10,367 which binds to FKBPs but does not inhibit calcineurin. Both molecules exert the same neuroprotective effect after H(2)O(2) 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. (3) 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. (4) 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.
Klettner
Alexa
A
Christian-Albrechts-University of Kiel, Institute of Pharmacology, Hospitalstrasse 4, 24105 Kiel, Germany. damm@pharmakologie.uni-kiel.de
Herdegen
Thomas
T
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006360:Heat-Shock Proteins / Q000819:agonists / Q000096:biosynthesis; D018869:Heat-Shock Response / Q000187:drug effects* / Q000502:physiology*; D020104:Immunophilins / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology*
D006360:Heat-Shock Proteins; D008024:Ligands; D018696:Neuroprotective Agents; D011725:Pyridines; C108850:V 10367; D020104:Immunophilins; D016559:Tacrolimus