Abstract
Limited axon regeneration following peripheral nerve injury may be
related to activation of the lysosomal protease, asparaginyl
endopeptidase (AEP, δ-secretase), and its degradation of the microtubule
associated protein, Tau. Activity of AEP was increased at the site of
sciatic nerve transection and repair but blocked in mice treated
systemically with a specific AEP inhibitor, compound 11 (CP11).
Treatments with CP11 enhanced axon regeneration in vivo .
Amplitudes of compound muscle action potentials recorded four weeks
after nerve transection and repair and two weeks after daily treatments
with CP11 were double those of vehicle-treated mice. At that time after
injury, axons of significantly more motor and sensory neurons had
regenerated successfully and reinnervated the tibialis anterior and
gastrocnemius muscles in CP11-treated mice than vehicle-treated
controls. In cultured adult dorsal root ganglion neurons derived from
wild type mice that were treated in vitro for 24 hours with CP11,
neurites were nearly 50% longer than in vehicle-treated controls, and
similar to neurite lengths in cultures treated with the TrkB agonist,
7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF
did not enhance outgrowth more than treatments with either one alone.
Enhanced neurite outgrowth produced by CP11 was found also in the
presence of the TrkB inhibitor, ANA-12, indicating that the enhancement
was independent of TrkB signaling. Longer neurites were found after CP11
treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by
CP11 is a treatment for peripheral nerve injury with great potential.