Vol. 282, Issue 2, 1084-1093, 1997

Comparative Dose-Dependence Study of FK506 and Cyclosporin A on the Rate of Axonal Regeneration in the Rat Sciatic Nerve

M.-S. Wang, Michelle Zeleny-Pooley and Bruce G. Gold¹

Center for Research on Occupational and Environmental Toxicology (M.-S.W., M.Z.-P., B.G.G.) and Department of Cell and Developmental Biology (B.G.G.), Oregon Health Sciences University, Portland, Oregon

The new immunosuppressant drug FK506 (Tacrolimus) increases the rate of nerve regeneration in vivo (; ). In the present study, we have examined the dose-dependence of FK506's ability to enhance nerve regeneration. In the first set of experiments, rats received daily s.c. injections of FK506 (2 mg/kg, 5 mg/kg or 10 mg/kg) for 18 days after a sciatic nerve crush injury. Signs of functional recovery in the hind feet appeared earlier than in saline-treated control rats at all three FK506 dosage; recovery was maximally accelerated in the 5-mg/kg group. Light microscopy at 18 days after nerve crush revealed more regenerating myelinated fibers in FK506-treated rats than in controls; this was most apparent in the 5-mg/kg group. Morphometric analysis of axonal areas in the soleus nerve confirmed that axonal calibers were maximally increased in the 5-mg/kg group. In the second set of experiments, the rate of axonal regeneration was determined by radiolabeling the L5 dorsal root ganglion. Regeneration rate for sensory axons was maximally increased (by 34%) in the 5-mg/kg group. In contrast, cyclosporin A (10 or 50 mg/kg; dosages were selected on the basis of the lower potency of cyclosporin A) did not significantly alter the rate of axonal regeneration. Cyclosporin A (50 mg/kg) also failed to increase functional recovery or axonal calibers in the soleus nerve. Because the two drugs share a common mechanism for producing immunosuppression (i.e., calcineurin inhibition), these results indicate that FK506's nerve regenerative property involves a distinct, calcineurin-independent mechanism.