Dose-dependent effects of FK506 on neuroregeneration in a rat model.
This study explored the effects of different doses of FK506 on peripheral nerve regeneration, to determine whether neuroregeneration could be enhanced without the toxicity of systemic immunosuppression. In the first part of the study, subimmunosuppressive doses of FK506 were determined by examining skin allograft survival in a rat model. Full-thickness skin grafts (2 cm2) from Wistar rats were grafted to recipient Lewis rats. The procedure was performed for six groups (n = 6). The control group received no FK506, and the other five groups received daily doses of FK506 of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg. Animals that received 2.0 mg/kg FK506 per day exhibited complete skin graft take, whereas all other groups demonstrated complete rejection. After determination of the immunosuppressive dose of FK506, the neuroregenerative effects of different doses of FK506 were explored by assessing nerve regeneration in 80 rats after tibial nerve transection and repair. The control group received no FK506, whereas the other four groups were given daily doses of FK506 of 0.25, 0.5, 1.0, or 2.0 mg/kg. Rats were euthanized at three time points (25, 30, and 35 days), to fully investigate the effects of different FK506 dosing regimens on neuroregeneration. Histomorphometric analyses performed on postoperative days 30 and 35 demonstrated statistically significant improvements in neuroregeneration with subimmunosuppressive FK506 doses of 0.5 and 1.0 mg/kg per day. Therefore, the study demonstrated that neuroregeneration was enhanced at low doses of FK506 that were not sufficient to prevent skin allograft rejection.
Yang
Roberta K
RK
Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Lowe
James B
JB
Sobol
Julia B
JB
Sen
Subhro K
SK
Hunter
Daniel A
DA
Mackinnon
Susan E
SE
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D023421:Models, Animal; D009416:Nerve Regeneration / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D016559:Tacrolimus