Early Regeneration Of Axons Following Peripheral Nerve Injury Is Enhanced If P75(Ntr)Is Eliminated From The Surrounding Pathway

The common neurotrophin receptor, p75(NTR), has been proposed to be an inhibitor of axon regeneration after peripheral nerve injury, but whether this effect is on the regenerating axons, immune cells migrating into the injury site, or cells in the pathway surrounding the axons is not clear. Cut nerves in mice expressing fluorescent proteins in axons were repaired with grafts from non-fluorescent hosts to study axon elongation when p75(NTR)was eliminated separately from axons and immune cells in the proximal stump of cut nerves, from cells in the regeneration pathway, or both. Two weeks later, axons from wild type mice regenerating into grafts devoid of p75(NTR)had elongated more than twice as far as axons in grafts from wild type mice. No enhancement of regeneration of axons in p75(NTR)knockout mice was observed, whether nerves were repaired with grafts from wild type mice or from p75(NTR)knockout mice. To evaluate whether inhibition of p75(NTR)could be used to improve regeneration, nerves in wild type mice repaired without grafts were exposed to a specific inhibitor of the p75(NTR)receptor, LM11A-31, at the time of nerve repair. This local blockade of p75(NTR)resulted in successful regeneration of axons of nearly three times as many motoneurons and reinnervation of twice as many muscle fibers by regenerating motor axons as untreated controls. Expression of p75(NTR)surrounding regenerating axons contributes to poor regeneration during the first 2 weeks after peripheral nerve injury. Inhibition of p75(NTR)might be a therapeutic target for treatments of peripheral nerve injuries.