Inhibition of nitric oxide synthase enhances peripheral nerve regeneration in mice

We tested the hypothesis that inhibition of nitric oxide synthase (NOS) following transection of the sciatic nerve in the mouse would adversely influence regeneration of myelinated fibers from the proximal stump. NOS was inhibited by N(omega)-nitro-L-arginine-methyl ester (L-NAME; 10 mg/kg i.p.), a broad spectrum NOS inhibitor given twice daily for the first 10 days following nerve transection in Swiss mice. Controls received the inactive enantiomer N(omega)-nitro-D-arginine methyl ester (D-NAME). Regeneration was assessed by serial recordings of the M potential from interosseous muscles of the foot innervated by sciatic-tibial motor fibers and morphometric analysis of myelinated fibers distal to the injury site. Contrary to expectation, M potentials reappeared earlier in the mice treated with L-NAME and were higher in amplitude (reflecting the number of reinnervating motor fibers) at 10 weeks after the injury. In the L-NAME treated mice, the mean axonal diameter of regenerating tibial myelinated fibers was larger and the fiber size histogram was shifted to larger fibers. Inhibition of NOS in a transected peripheral nerve is associated with enhanced regeneration of myelinated fibers. Local elaboration of NO may be toxic to regenerating axons.