Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats.
FK506 (tacrolimus), an immunosuppressant, reportedly reduces ischemic brain injury following transient middle cerebral artery occlusion (MCAO) in rats. The authors previously reported that the therapeutic window of FK506 in this model is more than 1 h, but less than 2 h. The aim of the present study is to determine whether mild hypothermia (35 degrees C) enhances the neuroprotective effects of FK506 and expands its therapeutic window. Sprague-Dawley rats were subjected to 2 h MCAO followed by 24 h reperfusion. Animals were randomly divided into four groups: (I) vehicle-treated normothermic group; (II) FK506-treated normothermic group; (III) vehicle-treated hypothermic group; (IV) FK506-treated hypothermic group. Animals received a single injection of FK506 (0.3 mg/kg) or vehicle intravenously at 2 h after ischemic induction. During ischemia, temporal muscle and rectal temperatures were maintained at 37 degrees C in the normothermic animals and at 35 degrees C in the hypothermic animals. Infarct volumes and neurological performance were evaluated at 24 h after reperfusion. The combination of FK506 and mild hypothermia significantly reduced infarct volume (cortex, -61%; striatum, -31%) and edema volume (cortex, -57%; striatum, -41%), while mild hypothermia or FK506 alone failed to improve ischemic brain damage. Furthermore, this combination also provided for the best functional outcome. These results demonstrate that the combination of FK506 and mild hypothermia significantly reduces ischemic brain damage following transient MCAO in rats, and expands the therapeutic window for FK506. This therapy may be a new approach for treatment of acute stroke.
Nito
Chikako
C
The Second Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo, Tokyo 113-8603, Japan. cnito@sk9.so-net.ne.jp
Kamiya
Tatsushi
T
Ueda
Masayuki
M
Arii
Takako
T
Katayama
Yasuo
Y
D000818:Animals; D001831:Body Temperature; D001929:Brain Edema / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D007036:Hypothermia, Induced; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D018696:Neuroprotective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D016559:Tacrolimus