Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury.
Traumatized axons possess an extremely limited ability to regenerate within the adult mammalian CNS. The myelin-derived axon outgrowth inhibitors Nogo, oligodendrocyte-myelin glycoprotein, and myelin-associated glycoprotein, all bind to an axonal Nogo-66 receptor (NgR) and at least partially account for this lack of CNS repair. Although the intrathecal application of an NgR competitive antagonist at the time of spinal cord hemisection induces significant regeneration of corticospinal axons, such immediate local therapy may not be as clinically feasible for cases of spinal cord injury. Here, we consider whether this approach can be adapted to systemic therapy in a postinjury therapeutic time window. Subcutaneous treatment with the NgR antagonist peptide NEP1-40 (Nogo extracellular peptide, residues 1-40) results in extensive growth of corticospinal axons, sprouting of serotonergic fibers, upregulation of axonal growth protein SPRR1A (small proline-rich repeat protein 1A), and synapse re-formation. Locomotor recovery after thoracic spinal cord injury is enhanced. Furthermore, delaying the initiation of systemic NEP1-40 administration for up to 1 week after cord lesions does not limit the degree of axon sprouting and functional recovery. This indicates that the regenerative capacity of transected corticospinal tract axons persists for weeks after injury. Systemic Nogo-66 receptor antagonists have therapeutic potential for subacute CNS axonal injuries such as spinal cord trauma.
Li
Shuxin
S
Department of Neurology and Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Strittmatter
Stephen M
SM
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019771:Axotomy; D001522:Behavior, Animal; D055233:Cornified Envelope Proline-Rich Proteins; D005260:Female; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007279:Injections, Subcutaneous; D020646:Intralaminar Thalamic Nuclei / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009185:Myelin Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects; D000070816:Nogo Receptor 1; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014176:Protein Biosynthesis; D011506:Proteins; D011712:Pyramidal Tracts / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000502:physiology; D012701:Serotonin; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy*
D055233:Cornified Envelope Proline-Rich Proteins; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D009185:Myelin Proteins; C499213:NEPI-40 protein, mouse; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; D011506:Proteins; D011956:Receptors, Cell Surface; C419790:Rtn4r protein, mouse; C486581:Rtn4r protein, rat; D012701:Serotonin