Neurotmesis, the most severe form of peripheral nerve injury, involves complete transection and loss of motor and sensory function. Surgical repair, typically via end-to-end neurorrhaphy (NRR), is often required. A key pathological feature is Wallerian degeneration (WD) in the distal stump, which, along with slow axonal regeneration, leads to muscle atrophy and poor functional recovery. Polyethylene glycol (PEG)-mediated axonal fusion has emerged as a promising strategy to bypass WD by rapidly reconnecting severed axons and restoring conduction. Methylene blue (MB) has previously enhanced PEG-fusion outcomes. This study investigated whether TEMPOL (TMP), a potent antioxidant, could further improve PEG-fusion-mediated repair following sciatic nerve transection in rats. Adult female Lewis rats underwent unilateral sciatic nerve transection and were randomly assigned to one of three groups: end-to-end neurorrhaphy (NRR), MB-PEG-fusion (MB-fusion), or TEMPOL-PEG-fusion (TMP-fusion). Functional recovery was assessed for 8 weeks using CatWalk gait analysis (Peroneal Functional Index, PFI). Electrophysiological recordings (CMAPs) were obtained at baseline, immediately post-repair, and at 8 weeks. Histological and immunofluorescence analyses (neurofilament, S100, synaptophysin, GFAP, Iba-1) were performed to evaluate axonal integrity, Schwann cell activity, synaptic coverage, and glial response. TMP-fusion significantly improved motor recovery compared to MB-fusion and NRR. Animals treated with TMP-fusion demonstrated superior sensorimotor function by week 8 (PFI; p = 0.0232, step sequence; p p p p = 0.0004), and reduced glial activation (Iba-1, p = 0.0035; GFAP, p = 0.001) compared to NRR. Synaptic integrity in the spinal cord was better maintained in the TMP-fusion group, indicating a more complete restoration of neuromuscular connectivity (p p = 0.0003). TEMPOL-PEG-fusion significantly enhances structural and functional recovery after neurotmesis, outperforming current gold-standard techniques. These results support TMP-fusion as a promising strategy for peripheral nerve repair.
Salamanca-Guillén et al. (Fri,) studied this question.