Cyclosporin A, but not FK506, prevents the downregulation of phosphorylated Akt after transient focal ischemia in the rat.
The two immunosuppressants, cyclosporin A (CsA) and FK506, when given 1 and 3 h after the start of reperfusion following 2 h of middle cerebral artery (MCA) occlusion, reduce infarct volume to 30% of control. This suggests a common effect, e.g. one due to suppression of the activation of calcineurin. However, when given by the intracarotid (i.c.) route after only 5 min of recirculation CsA, but not FK506, reduced infarct volume even further, to 10% of control. This was attributed to the fact that CsA, but not FK506, block the in vitro assembly of a mitochondrial permeability transition (MPT) pore. The present experiments were undertaken to further characterize the anti-ischemic effect of CsA, when given i.c. 5 min after recirculation and to explore why CsA, when given at that time, is more efficacious than FK506. It was established that the i.c. administration of CsA in a dose of 10 mg/kg increased the tissue concentration of CsA 2- to 3-fold, when compared to the i.v. administration. CsA proved to be effective in reducing infarct volume even when the tissue damage was assessed by histopathology after 7 days of recovery. MCA occlusion of 2 h duration caused a sustained decrease in the phosphorylation Akt at threonine 308. Since this down regulation of Akt was prevented by CsA, the results suggested a link between dephosphorylaltion of Bad, and cell death. Interestingly FK506 did not prevent down regulation of Akt, it thus seems unlikely that the anti-ischemic effect of CsA is related to its association with cytosolic cyclophilin.
Yoshimoto
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T
Center for the Study of Neurological Disease, Neuroscience Institute, Queen's Medical Center, Honolulu, HI, USA.
Uchino
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H
He
Q P
QP
Li
P A
PA
Siesjö
B K
BK
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D011518:Proto-Oncogene Proteins; D016572:Cyclosporine; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D016559:Tacrolimus