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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 282; no. 2; pp. 1084 - 1093
• Main Authors: Wang, M S, Zeleny-Pooley, M, Gold, B G
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.1997
• Subjects: Animals; Axons - drug effects; Axons - physiology; Axons - ultrastructure; Cyclosporine - administration & dosage; Cyclosporine - pharmacology; Dose-Response Relationship, Drug; Male; Microscopy, Electron; Nerve Regeneration - drug effects; Rats; Rats, Sprague-Dawley; Sciatic Nerve - drug effects; Sciatic Nerve - physiology; Sciatic Nerve - ultrastructure; Tacrolimus - administration & dosage; Tacrolimus - pharmacology
• ISSN: 0022-3565; 1521-0103

The new immunosuppressant drug FK506 (Tacrolimus) increases the rate of nerve regeneration in vivo ( Gold et al. , 1994 ; Gold et al. , 1995 ). 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.