Nogo-66 receptor antagonist peptide promotes axonal regeneration

Nature. 2002 May 30;417(6888):547-51. doi: 10.1038/417547a.


Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of axonal regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes and can inhibit axonal outgrowth through an axonal Nogo-66 receptor (NgR). The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1 40) antagonist peptide (NEP1 40) blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1 40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Axons / drug effects*
  • Axons / pathology
  • Axons / physiology
  • Binding, Competitive
  • Central Nervous System / cytology
  • Central Nervous System / drug effects
  • Central Nervous System / physiology
  • Culture Media, Conditioned / pharmacology
  • Female
  • GPI-Linked Proteins
  • Growth Cones / drug effects
  • Growth Cones / physiology
  • Molecular Sequence Data
  • Motor Activity / drug effects
  • Myelin Proteins / chemistry
  • Myelin Proteins / pharmacology
  • Myelin Proteins / therapeutic use
  • Myelin Sheath / physiology
  • Nerve Regeneration / drug effects*
  • Neurites / drug effects
  • Neurites / physiology
  • Nogo Receptor 1
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Peptide Fragments / therapeutic use
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism
  • Spinal Cord Injuries / drug therapy
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / physiopathology


  • Culture Media, Conditioned
  • GPI-Linked Proteins
  • Myelin Proteins
  • NEPI-40 protein, rat
  • Nogo Receptor 1
  • Peptide Fragments
  • Receptors, Cell Surface
  • Rtn4r protein, rat