title: FK506 ameliorates oxidative damage and protects rat brain following transient focal cerebral ischemia.
abstract: OBJECTIVE
  The immunosuppressant FK506 (tacrolimus) is neuroprotective in experimental models of cerebral ischemia. However, the precise mechanisms underlying this neuroprotection remain unknown. In the present study, we hypothesized that FK506 treatment could  protect rat brain from oxidative injuries through antioxidative and anti-inflammatory pathways after ischemia-reperfusion injury.
  
  
  METHODS
  Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 120 minutes, followed by reperfusion. Animals received  a single injection of FK506 (0·3 mg/kg) or vehicle intravenously at 30 minutes after ischemic induction. Infarct volume and neurological performance were evaluated at 24 hours after reperfusion. Immunohistochemical analysis for 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-deoxyguanosine (8-OHdG),  ionized calcium-binding adapter molecule 1 (Iba-1), and tumor necrosis factor-alpha (TNF-alpha) were conducted at 24 hours after reperfusion.
  
  
  RESULTS
  FK506 significantly reduced infarct volume (61·7%; P=0·01) and improved neurological deficit scores  (P<0·05) 24 hours after reperfusion compared to vehicle. In FK506-treated rats, accumulation of 4-HNE (P<0·01) and 8-OHdG (P<0·01) was significantly suppressed in the cerebral cortex 24 hours after reperfusion. In addition, FK506 markedly  reduced microglial activation (P<0·01) and TNF-alpha expression (P<0·01).
  
  
  CONCLUSIONS
  These results demonstrate that FK506 may have antioxidant as well as anti-inflammatory effects and reduces ischemic damage following cerebral infarction.
authors: Department of Internal Medicine, Division of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan. cnito@nms.ac.jp
authors: Chikako
authors: C
authors: Nito
authors: Masayuki
authors: M
authors: Ueda
authors: Toshiki
authors: T
authors: Inaba
authors: Ken-Ichiro
authors: K
authors: Katsura
authors: Yasuo
authors: Y
authors: Katayama
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D000447:Aldehydes; D000975:Antioxidants; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal; D016559:Tacrolimus