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J Thorac Cardiovasc Surg 2005;129:123-128
© 2005 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits

^a Department of Cardiovascular Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
^b Department of Functional Morphology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Received for publication December 30, 2003; revisions received April 20, 2004; accepted for publication April 22, 2004.

^* Address for reprints: Norihiko Shiiya, MD, PhD, Department of Cardiovascular Surgery, Hokkaido University Hospital, N14, W5, Kita-ku, Sapporo 060-8648, Japan (E-mail: shiyanor{at}med.hokudai.ac.jp).

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.

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