Calcineurin and cyclophilin D are differential targets of neuroprotection by immunosuppressants CsA and FK506 in ischemic brain damage.
The search for an effective treatment for global ischemia following cardiac arrest has proved to be very difficult. However, studies by Uchino et al. show that the immunosuppressant cyclosporin A (CsA), when administered in such a way that the drug can bypass the blood brain barrier (BBB), dramatically reduces ischemic damage in rat forebrain preparations. An alternative immunosuppressant, FK506, is apparently less efficacious. Both CsA and FK506 are specific inhibitors of immunophilins, (CsA inhibits cyclophilins, FK506 inhibits FKBPs), and of calcineurin, a type 2B Ser/Thr phosphatase that is abundant in the central nervous system. The superiority of CsA may be partly attributable to its selective amelioration of mitochondrial damage, as assayed in vivo and in vitro. Our results suggest that pathways involving calcineurin and cyclophilins, particularly mitochondrial cyclophilin D, play pivotal roles in the development of ischemic brain damage. The present findings may inform the search for new drugs in the treatment of global ischemic damage to the brain, and in other organs.
Uchino
H
H
Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Hachioji, Japan. huchino@hotmail.com
Ishii
N
N
Shibasaki
F
F
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology*; D045304:Cytochromes c / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008933:Mitochondrial Swelling / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D016548:Prosencephalon / Q000098:blood supply; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*; D051025:bcl-Associated Death Protein
C494821:Bad protein, rat; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D051025:bcl-Associated Death Protein; D016572:Cyclosporine; D045304:Cytochromes c; D019703:Calcineurin; D021983:Cyclophilins; D002118:Calcium; D016559:Tacrolimus