Effect of chronic cyclosporine administration on peripheral nerve regeneration: a dose-response study.
An experimental study was conducted to investigate the effect of chronic cyclosporine A (CsA) administration with different doses on peripheral nerve regeneration. Forty adult male Lewis rats weighing 150 to 200 g were used. The right sciatic nerve was transected 1 cm distal to the sciatic notch, and a conventional end-to-end nerve coaptation was performed. According to the daily dose of subcutaneous CsA injections, animals were randomized into one control group and four experimental groups of 8 animals each (group I, control with no treatment; group II, 2 mg per kilogram CsA; group III, 4 mg per kilogram CsA; group IV, 8 mg per kilogram CsA; and group V, 16 mg per kilogram CsA). Daily injections of CsA were administered for 12 weeks by an investigator blinded to the different treatment groups. At 3, 6, and 12 weeks after nerve repair, motor recovery was evaluated by the toe spread test, and sensory recovery was measured using the pin-prick test and somatosensory evoked potentials (SEPs). Evaluations were performed by an investigator who was blinded to the treatment groups. At 12 weeks, sciatic nerve samples were harvested for histomorphometric analysis. Motor recovery was retarded regardless of CsA dose at each time point of evaluation. Sensory recovery was only delayed in the 16-mg-per-kilogram CsA treatment group at the 3 week follow-up. SEP results revealed significantly prolonged N2 and P1 latencies in all CsA treatments regardless of dose and time frame of evaluation compared with the control group (p < 0.05). Histomorphometric analysis demonstrated significantly reduced numbers of myelinated axons, reduced myelin sheath thickness, and reduced diameters in all CsA treatment groups compared with the control group (p < 0.05). Based on these findings in this experimental model of sciatic nerve, the authors conclude that CsA overall had direct deleterious effects on peripheral nerve regeneration as demonstrated by SEP, pin-prick test, toe spread test, and histomorphometric nerve analysis. These adverse effects seemed to be dose related for sensory recovery only at 3 and 6 weeks of CsA exposure after nerve repair. Motor recovery was affected negatively by short- and long-term CsA administration regardless of dose.
Meirer
Romed
R
Departments of Plastic and Reconstructive Surgery and Neurology, The Cleveland Clinic Foundation, OH 44195, USA.
Babuccu
Orhan
O
Unsal
Murat
M
Nair
Dileep R
DR
Gurunluoglu
Raffi
R
Skugor
Blazenka
B
Meirer
Bettina
B
Siemionow
Maria
M
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005073:Evoked Potentials, Somatosensory; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects*; D051381:Rats; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000473:pathology / Q000502:physiology* / Q000601:surgery; D013997:Time Factors
D007166:Immunosuppressive Agents; D016572:Cyclosporine