Systemic hypoxia mimicry enhances axonal regeneration and functional recovery following peripheral nerve injury

Exp Neurol. 2020 Dec:334:113436. doi: 10.1016/j.expneurol.2020.113436. Epub 2020 Aug 16.


Despite the ability of peripheral nerves to regenerate after injury, failure occurs due to an inability of supporting cells to maintain growth, resulting in long-term consequences such as sensorimotor dysfunction and neuropathic pain. Here, we investigate the potential of engaging the cellular adaptive response to hypoxia, via inhibiting its negative regulators, to enhance the regenerative process. Under normoxic conditions, prolyl hydroxylase domain (PHD) proteins 1, 2, and 3 hydroxylate the key metabolic regulator hypoxia inducible factor 1α (HIF1α), marking it for subsequent proteasomal degradation. We inhibited PHD protein function systemically via either individual genetic deletion or pharmacological pan-PHD inhibition using dimethyloxalylglycine (DMOG). We show enhanced axonal regeneration after sciatic nerve crush injury in PHD1-/- mice, PHD3-/- mice, and in DMOG-treated mice, and in PHD1-/- and DMOG-treated mice a reduction in hypersensitivity to cooling after permanent sciatic ligation. Electromyographically, PHD1-/- and PHD3-/- mice showed an increased CMAP amplitude one-month post-injury, probably due to protection against denervation induced muscle atrophy, while DMOG-treated and PHD2+/- mice showed reduced latencies, indicating improved motor axon function. DMOG treatment did not affect the growth of dorsal root ganglion neurites in vitro, suggesting a lack of direct effects of DMOG on axonal regrowth. Enhanced regeneration in vivo was concurrent with an increase in macrophage density, and a shift in macrophage polarization state ratios (from M1-like toward M2-like) in DMOG-treated animals. These results indicate PHD proteins as a novel therapeutic target to improve regenerative and functional outcomes after peripheral nerve injury without manipulating molecular O2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology
  • Amino Acids, Dicarboxylic / therapeutic use
  • Animals
  • Axons / drug effects
  • Axons / physiology*
  • Cells, Cultured
  • Hypoxia / drug therapy
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / physiology*
  • Peripheral Nerve Injuries / drug therapy
  • Peripheral Nerve Injuries / metabolism*
  • Peripheral Nerve Injuries / pathology
  • Prolyl Hydroxylases / metabolism
  • Prolyl-Hydroxylase Inhibitors / pharmacology
  • Prolyl-Hydroxylase Inhibitors / therapeutic use
  • Recovery of Function / drug effects
  • Recovery of Function / physiology*


  • Amino Acids, Dicarboxylic
  • Prolyl-Hydroxylase Inhibitors
  • Prolyl Hydroxylases
  • oxalylglycine

Grants and funding