FK506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat

We examined the efficacy of FK506 in reducing tissue damage after spinal cord injury in comparison to methylprednisolone (MP) treatment. Rats were subjected to a photochemical injury (T8) and were given a bolus of MP (30 mg/kg), FK506 (2 mg/kg), or saline. An additional group received an initial bolus of FK506 (2 mg/kg) followed by daily injections (0.2 mg/kg intraperitoneally). Functional recovery was evaluated using open-field walking, inclined plane tests, motor evoked potentials (MEPs), and the H-reflex response during 14 days post-operation (dpo). Tissue sparing and glial fibrillary acidic protein (GFAP), biotinylated tomato lectin LEG, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and interleukin 1β (IL-1β) immunoreactivity were quantified in the injured spinal cord. FK506-treated animals demonstrated significantly better neurologic outcome, higher MEP amplitudes, and lower H-wave amplitude compared to that of saline-treated rats. In contrast, administration of MP did not result in significant differences with respect to the saline-treated group. Histologic examination revealed that tissue sparing was largest in FK506-treated compared to saline and MP-treated animals. GFAP and COX-2 reactivity was decreased in animals treated with FK506 compared to that in animals given MP or saline, whereas IL-1β expression was similarly reduced in both FK506- and MP-treated groups. Microglia/macrophage response was reduced in FK506 and MP-injected animals at 3 dpo, but only in MP-treated animals at 7 dpo with respect to saline-injected rats. Repeated administrations of FK506 improved functional and histologic results to a greater degree than did a single bolus of FK506. The results indicate that FK506 administration protects the damaged spinal cord and should be considered as potential therapy for treating spinal cord injuries. © 2005 Wiley-Liss, Inc.