Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rat: therapeutic time window for FK506 in transient focal ischemia.
Tacrolimus (FK506), an immunosuppressant currently used in clinic, is known to have neuroprotective properties. However, effects in focal ischemia are shown only in a endothelin induced middle cerebral artery (MCA) occlusion model or with filament technique at a relatively high dose. We have previously shown that FK506 had significant protective effects at a low dose of 0.3 mg kg(-1) when administered immediately after ischemia. In this study, we explored the therapeutic time window of FK506 at this low dose, in a transient focal ischemia model using filament technique. Male Sprague-Dawley rats were subjected to 2 h MCA occlusion and subsequent reperfusion. They received FK506 or vehicle (0.3 mg kg(-1)) i.v. at 30, 60 or 120 min after induction of ischemia, and were decapitated 24 h after ischemia. FK506 injected at 30 and 60 min significantly reduced cortical infarction volume (FK506 vs. vehicle; 30 min: 95 +/- 33 mm3 vs. 170 +/- 62 mm3, p < 0.05; 60 min: 93 +/- 45 mm3, vs. 168 +/- 35 mm3, p < 0.05, respectively). FK506 was ineffective when given at 120 min after ischemia. FK506 had no effect on edema formation, nor on the infarct volume in striatum. The therapeutic time window for this low dose of FK506 given i.v. is between 60 and 120 min in this model.
Arii
T
T
The Second Department of Internal Medicine, Nippon Medical School, Tokyo, Japan. ariitaka@nms.ac.jp
Kamiya
T
T
Arii
K
K
Ueda
M
M
Nito
C
C
Katsura
K I
KI
Katayama
Y
Y
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004334:Drug Administration Schedule; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016559:Tacrolimus / Q000494:pharmacology*; D016896:Treatment Outcome
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D016559:Tacrolimus