Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia.
The immunosuppressive action of the drug FK506 involves inhibition of calcineurin in T-lymphocytes by a complex of FK506 and an FK506 binding protein, FKBP12, a member of the immunophilin protein family. The functional role of brain immunophilins is, however, unclear. We show here that FK506 is a powerful neuroprotective agent in an in vivo model of focal cerebral ischaemia when administered up to 60 min post-occlusion. The minimum effective neuroprotective dose is comparable with the immunosuppressant dose in humans, suggesting that FK506 may have clinical potential for the treatment of stroke. Although the related immunosuppressants rapamycin and cyclosporin failed to reduce brain damage, the finding that rapamycin pretreatment blocked the effect of FK506 confirms a role for immunophilins in the neuroprotective mechanism.
Sharkey
J
J
Fujisawa Institute of Neuroscience, Department of Pharmacology, University of Edinburgh, UK.
Butcher
S P
SP
D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D002352:Carrier Proteins / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D011090:Polyenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus