FK506 enhances reinnervation by regeneration and by collateral sprouting of peripheral nerve fibers.

We examined the effects of FK506 administration on the degree of target reinnervation by regenerating axons (following sciatic nerve crush) and by collateral sprouts of the intact saphenous nerve (after sciatic nerve resection) in the mouse. FK506-treated animals received either 0.2 or 5 mg/kg/day, dosages previously found to maximally increase the rate of axonal regeneration in the mouse. Functional reinnervation of motor, sensory, and sweating activities was assessed by noninvasive methods in the hind paw over a 1-month period following lesion. Morphometric analysis of the regenerated nerves and immunohistochemical labeling of the paw pads were performed at the end of follow-up. In the sciatic nerve crush model, FK506 administration shortened the time until target reinnervation and increased the degree of functional and morphological reinnervation achieved. The recovery achieved by regeneration was greater overall with the 5 mg/kg dose than with the dose of 0.2 mg/kg of FK506. In the collateral sprouting model, reinnervation by nociceptive and sudomotor axons was enhanced by FK506. Here, the field expansion followed a faster course between 4 and 14 days in FK506-treated animals. In regard to dose, while collateral sprouting of nociceptive axons was similarly increased at both dosages (0.2 and 5 mg/kg), sprouting of sympathetic axons was more extensive at the high dose. This suggests that the efficacy of FK506 varies between subtypes of neurons. Taken together, our findings indicate that, in addition to an effect on rate of axonal elongation, FK506 improves functional recovery of denervated targets by increasing both regenerative and collateral reinnervation.