Efficacy of Short-Term FK506 Administration on Accelerating Nerve Regeneration

Abstract

Background. The slow rate of nerve regeneration following injury can cause extended muscle denervation, leading to irreversible muscle atrophy, fibrosis, and destruction of motor endplates. The immunosuppressant FK506 (tacrolimus) has been shown to accelerate the rate of nerve regeneration and functional recovery. However, the toxic and immunosuppressive properties of FK506 make it undesirable for long-term use. Objective. To take advantage of the regeneration-enhancing effects of FK506 but avoid the potential adverse effects of long-term administration, the current study evaluates and quantifies the efficacy of short-term FK506 treatment in rat models. Methods. Clinically relevant transection and graft models were evaluated, and walking track analysis (WTA) was used to evaluate functional recovery. FK506 was administered for 5 and 10 days post transection injury and 10 and 20 days post graft injury. Both groups involving a short course were compared with the continuous administration group. Results. In the transection model, FK506 was administered for 5 and 10 days postoperatively. WTA demonstrated that 10 days of FK506 administration was sufficient to reduce functional recovery time by 29% compared with negative controls. In the graft model, FK506 was administered for 10 and 20 days postoperatively. Short treatment courses of 10 and 20 days reduced recovery time by 15% and 21%, respectively, compared with negative controls. Analysis of blood–nerve barrier (BNB) integrity demonstrated that FK506 facilitated early reconstitution of the BNB. Conclusions. The results of this study indicate that short-term FK506 delivery following nerve injury imparts a significant therapeutic effect.