Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits.
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.
Tachibana
Tsuyoshi
T
Department of Cardiovascular Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Shiiya
Norihiko
N
Kunihara
Takashi
T
Wakamatsu
Yutaka
Y
Kudo
Akimaro Fabio
AF
Ooka
Tomonori
T
Watanabe
Satoshi
S
Yasuda
Keishu
K
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*
D018696:Neuroprotective Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus