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Treatments with the specific δ-secretase inhibitor, compound 11, promote the regeneration of motor and sensory axons after peripheral nerve injury.
  • +6
  • Robin Isaacson,
  • Dario Carrasco,
  • Hannah Holliday,
  • Seong Kang,
  • Samia Khan,
  • David Kim,
  • Xia Liu,
  • Keqiang Ye,
  • Arthur English
Robin Isaacson
Emory University School of Medicine
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Dario Carrasco
Emory University School of Medicine
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Hannah Holliday
Emory University School of Medicine
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Seong Kang
Emory University School of Medicine
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Samia Khan
Emory University School of Medicine
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David Kim
Emory University School of Medicine
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Xia Liu
Emory University School of Medicine
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Keqiang Ye
Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences
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Arthur English
Emory University School of Medicine

Corresponding Author:medae@emory.edu

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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.
31 May 2023Submitted to European Journal of Neuroscience
01 Jun 2023Submission Checks Completed
01 Jun 2023Assigned to Editor
01 Jun 2023Review(s) Completed, Editorial Evaluation Pending
04 Jun 2023Reviewer(s) Assigned
08 Jul 2023Editorial Decision: Revise Minor
21 Jul 20231st Revision Received
21 Jul 2023Submission Checks Completed
21 Jul 2023Assigned to Editor
21 Jul 2023Review(s) Completed, Editorial Evaluation Pending
21 Jul 2023Reviewer(s) Assigned
09 Aug 2023Editorial Decision: Accept