title: Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits.
abstract: BACKGROUND
  We comparatively evaluated the protective effect of the immunophilin ligands cyclosporine A (INN: ciclosporin), FK506, and rapamycin on the spinal cord in a rabbit model of transient ischemia. Both cyclosporine A and FK506 inhibit calcineurin, whereas rapamycin does not.
  
  
  METHODS
  Thirty-six male New Zealand White rabbits were divided into the following 6 groups: group C, 15 minutes of spinal cord ischemia; group FK, FK506 (1 mg/kg) administered 30 minutes before ischemia; group CsA, cyclosporine A (30 mg/kg) administered 30 minutes before ischemia; group CsA-C, chronic administration of cyclosporine A (20 mg/kg) for 9 days before ischemia; group R, rapamycin (1 mg/kg) administered 30 minutes before ischemia; and group R+FK, rapamycin (1 mg/kg) administered 20 minutes before FK506 pretreatment (1 mg/kg). Group CsA-C was added because the drug does not readily cross the blood-brain barrier. Neurologic function was evaluated by Johnson's 5-point scale at 8, 24, and 48 hours after ischemia, and histopathology was assessed 48 hours after ischemia.
  
  
  RESULTS
  At 24 and 48 hours after ischemia, the Johnson score was better in groups FK (4.0 +/- 1.1), R+FK (3 +/- 1.1), and CsA-C (2.7 +/- 1.2) than in group C (0.8 +/- 1.2). Numbers of morphologically intact anterior horn cells were higher in groups FK (31.3 +/- 9.9), R+FK (23.2 +/- 4.5), and CsA-C (18.3 +/- 6.8) than in group C (6.3 +/- 4.3).
  
  
  CONCLUSIONS
  FK506 and chronic administration of cyclosporine A, but not rapamycin, protect the spinal cord from transient ischemia. Although these results are compatible with inhibition of calcineurin in the mechanism of neuroprotective action of these drugs, other effects through different pathways cannot be excluded before further study.
authors.affiliation: Department of Cardiovascular Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Tachibana
authors.forename: Norihiko
authors.initials: N
authors.lastname: Shiiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Kunihara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Wakamatsu
authors.forename: Akimaro Fabio
authors.initials: AF
authors.lastname: Kudo
authors.forename: Tomonori
authors.initials: T
authors.lastname: Ooka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Watanabe
authors.forename: Keishu
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D000818:Animals; D001259:Ataxia / Q000175:diagnosis / Q000453:epidemiology; D001707:Biopsy, Needle; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D007150:Immunohistochemistry; D008297:Male; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology; D010243:Paralysis / Q000175:diagnosis / Q000453:epidemiology; D020335:Paraparesis / Q000175:diagnosis / Q000453:epidemiology; D011336:Probability; D011817:Rabbits; D011897:Random Allocation; D012307:Risk Factors; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000494:pharmacology*; D020760:Spinal Cord Ischemia / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D018709:Statistics, Nonparametric; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus