Bimodal dose-dependence of FK506 on the rate of axonal regeneration in mouse peripheral nerve.

Abstract

FK506 has been shown to enhance the rate of axonal regeneration after peripheral nerve lesions. However, quite variable doses of FK506 have been used in different animal studies. We examined the dose-dependence of FK506 on the rate of axonal regeneration after crush lesion of the mouse sciatic nerve. Mice received daily subcutaneous injections of FK506 at 0.2, 0.5, 1, 2, 5, or 10 mg/kg for 7 days after lesioning. A control group was injected with saline. The distance that regenerative axons advanced from the crush site was measured by the pinch test at 2, 4, and 7 days. Regenerating axons reached greater mean distances in all FK506-treated groups compared to the control group. The fastest regeneration rate was found at 5 mg/kg (12% increase over controls), although the 0.2 and 2 mg/kg doses achieved similar regeneration rates. In contrast, intermediate doses (0.5 and 1 mg/kg) and a higher dose (10 mg/kg) were not different from controls. Calcitonin gene-related peptide immunohistochemical labeling of regenerating axons yielded similar results to those found with the pinch test. Based on our finding of a double peak in the dose-response for FK506, it is hypothesized that at least two mechanisms of action (perhaps corresponding to distinct functional binding sites) are evoked at different concentrations of the drug to accelerate nerve regeneration. These results have clinical implications for the pharmacological treatment of nerve injuries while avoiding immunosuppressive effects and for the design of related drugs with more specific activities.