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Page 4 of 13 Chi et al. Plast Aesthet Res 2023;10:56 https://dx.doi.org/10.20517/2347-9264.2023.48

[33]
FK506 action since the FK506 neurotrophic effect is dependent on functioning FKBP-52 . FKBP-52 has
well-described roles in cytoplasmic microtubule shuttling and closely interacts with steroid receptors,
suggesting that steroid receptor signaling and intracellular transport may play important roles in peripheral
[34]
nerve regeneration .

FK506 side effects
The clinical applications of FK506 remain limited since its mode of delivery has traditionally been systemic
administration with an ensuing severe side effect profile. Among these include nephrotoxicity,
hyperglycemia, and central nerve system effects that can manifest as headache, nausea, seizures, and
tremor [35,36] . Prolonged weight loss secondary to diarrhea and other gastrointestinal disturbances has also
[25]
been reported . Given its role as an immunosuppressant, prolonged use of tacrolimus results in greater
risks of infection (opportunistic infections) and cancer (skin and lymphoproliferative malignancies) from
decreased immune monitoring. This adverse side effect profile requires the optimization of drug dosing,
timing, and mode of delivery for tacrolimus to be used in peripheral nerve injury.

FK506 administration
For transplant patients, tacrolimus dosing is carefully modulated to maintain a steady-state tacrolimus
trough levels of 5.0-15.0 ng/mL depending on the transplant organs involved and other immunosuppressive
[37]
agents given that corresponds to human doses of roughly 0.1-0.2 mg/kg/day . Interestingly, translational
studies have demonstrated that FK506 may have multiple dose levels to implement improved
neuroregeneration. When investigating 6 different levels of tacrolimus dosing after mouse sciatic nerve
crush injuries compared to saline controls, the intermediate doses had no efficacy in improving
regeneration rate, implying some bimodal dose efficacy . To examine if improved nerve regeneration
[29]
could take place at sub-immunosuppressive doses of FK506, full-thickness skin grafts from a different rat
species were performed, and efficacious doses of 0.5 and 1 mg/kg/day of FK506 improved tibial nerve
regeneration after transection and repair also resulted in concomitant complete rejection of the skin
[38]
graft . These findings raise the clinical question as to whether these sub-immunosuppressive doses of
FK506 could be administered to peripheral nerve injury patients and ameliorate the adverse side effect
profile. The senior author has used this drug with a small number of patients with autograft reconstruction,
treating them with FK506 for one year with no systemic complications and excellent neurological recovery
(unpublished). The medication timing schedule and appropriate dosing in these cases are patient-specific,
given the pharmacokinetics, pharmacodynamics, and multiple drug-drug interactions that require close
coordination with our immunology and transplant medicine colleagues.

The advent of upper extremity transplantation has thus allowed an opportunity to assess the
neuroregenerative potential of tacrolimus in a clinically-indicated setting. The first hand transplantation
performed in America was noted for more rapid nerve regeneration assessed by Tinel’s sign than previously
[39]
expected from hand replants with an average regeneration rate of 2 mm/day . With nerve coaptations
performed 15 cm proximal to the wrist crease, Tinel’s signs were present at the fingertips within 6 months,
having traversed a > 30 cm distance. A European group went on to report that in their hand transplantation
with nerve coaptations 21 cm proximal to the wrist crease, Tinel’s sign had advanced to the wrist crease
within 3 months (> 2 mm/day) . Building upon this work, tacrolimus was found to be beneficial in
[40]
utilizing nerve allograft transplantation with nerves prepared from consenting immunologically matched
donors. These nerves were transplanted into patients with long peripheral nerve gaps 12-37 cm in length
that were too long to be reconstructed using traditional nerve autografts. Nerve regeneration rates in these 7
patients receiving nerve allografts with immunosuppression were almost 2 mm/day . The increased nerve
[41]
regeneration rate of FK506 is demonstrated in [Figure 1].