[Stimulation of Schwann cell growth and axon regeneration of peripheral nerves by the immunosuppressive drug FK 506].
BACKGROUND
Nerve allografts are highly antigenic and, thus, require the continuous use of immunosuppressive drugs. The immunosuppressant Cyclosporine A was used in most studies. More recently, the immunosuppressive effect of FK 506 on peripheral nerve allografts and xenografts has been studied, and the drug has been found to prevent rejection successfully. However, neurotoxic complications have been noted in the central and peripheral nervous system although an increased rate of axonal regeneration has also been shown.


METHODS
Schwann cells were cultured from the sciatic nerve of the rat. The effect of 100 microM FK 506 administered daily on these cultures was assessed over a period of seven days and compared to an untreated control group of cultures. To visualize a direct effect of FK 506 on Schwann cells, the changes in intracellular calcium were recorded using fluorescence imaging of primary rat Schwann cell cultures loaded with Fluo-3. Regeneration of autologous nerve grafts was assessed in a rat model clinically and morphometrically after daily administration of 0.6 mg FK 506/kg body weight.


RESULTS
FK 506 increases the number of Schwann cells in culture significantly compared to the control group, while the fibrocyte population is decreased. FK 506 caused a transient increase of intracellular calcium levels of cultured cells. A significantly higher axon count was observed in the FK 506-treated grafts after two weeks of regeneration compared with controls. Additionally, less myelin debris was evident in the FK 506 treated group after two weeks compared with the control group. Good regeneration was noted in all grafts after six weeks of regeneration.


CONCLUSIONS
The increased axon counts and decreased myelin debris in the FK 506 grafts after two weeks indicate an accelerated Wallerian degeneration and increased axon sprouting into the graft initially. FK 506 promotes axonal regeneration through binding to FKBP-12, thus activating GAP-43 (growth associated protein) and the TGF beta 1-pathway (transforming growth factor). In addition, the increase of the intracellular calcium may induce Schwann cell proliferation via Calmodulin which in turn promotes axonal regeneration.
Fansa
H
H
Klinik für Plastische, Wiederherstellungs- und Handchirurgie, Medizinische Fakultät der Otto-von-Guericke-Universität in Magdeburg.
Keilhoff
G
G
Horn
T
T
Altmann
S
S
Wolf
G
G
Schneider
W
W
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D010525:Peripheral Nerves / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012583:Schwann Cells / Q000187:drug effects* / Q000502:physiology; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology / Q000637:transplantation; D016559:Tacrolimus / Q000494:pharmacology*; D014182:Transplantation, Autologous
D007166:Immunosuppressive Agents; D002118:Calcium; D016559:Tacrolimus