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Background: Chronic denervation resulting from long regeneration times and distances is a major contributor to suboptimal surgical outcomes following nerve injuries. We previously showed that nerve grafts from the side of an intact donor nerve into the side of a chronically injured nerve reverse these deleterious effects. The underlying regulators of this protective effect remain unknown. In this study we determine whether Neuregulin-1, a potent Schwann cell mitogen, regulates axonal regeneration in a rat peripheral nerve injury model. We selectively inhibit Neuregulin-1 signaling with Trastuzumab, a monoclonal antibody specifically blocking Neuregulin-1 s receptor, ErbB2.

Methods: The common peroneal nerves of 32 Lewis rats (16 saline; 16 Trastuzumab) were surgically transected and repaired. These injuries were allowed to heal for 2 or 4 weeks. Individual neurons were counted in the ventral horn of the spinal cord by dividing the healing nerve 1 cm from the repair site and exposing it to fluorescent dyes which are retrogradely transported to the neuron cell bodies. Histomorphometry was used to quantify fiber diameter and myelin thickness within the regenerating nerve.

Results: Significantly fewer neurons regenerated in rats treated with Trastuzumab (295 ± 19) compared with rats receiving saline (367 ± 23) at 2 weeks post repair (p < 0.05). No difference was observed at 4 weeks post-repair in rats treated with Trastuzumab (330 ± 11) compared to saline (336 ± 8). Mean regenerated fiber diameter (FD) and myelin thickness (MT) did not differ between rats treated with Trastuzumab (FD = 3.44 ± 0.06 um; MT = 0.51 ± 0.02 um) and those treated with Saline (FD = 3.35 ± 0.06 um; MT = 0.55 ± 0.02 um) at 4 weeks post-repair.

Conclusions: We conclude that Neuregulin-1 signaling is required for the early phase of axon regeneration following acute nerve injury and repair. This novel finding will play a key role in the development of surgical and pharmacological strategies directed at enhancing outcomes following nerve injury.