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PMID: 12764110 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 23 ·No. 10 ·2003-05-15 ·Pages 4219-27

Li S, Strittmatter SM

Abstract

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.

MeSH Terms
Amino Acid Sequence Animals Axons/drug effects,metabolism,physiology Axotomy Behavior, Animal Cornified Envelope Proline-Rich Proteins Female GPI-Linked Proteins Ganglia, Spinal/drug effects,metabolism,physiology Injections, Subcutaneous Intralaminar Thalamic Nuclei/drug effects,physiology Membrane Proteins Mice Mice, Inbred C57BL Molecular Sequence Data Molecular Weight Motor Activity/drug effects,physiology Myelin Proteins/administration & dosage,antagonists & inhibitors,chemistry,pharmacology,physiology,therapeutic use Nerve Fibers/drug effects,metabolism,physiology Nerve Regeneration/drug effects Nogo Receptor 1 Peptide Fragments/administration & dosage,chemistry,pharmacology,therapeutic use Protein Biosynthesis Proteins Pyramidal Tracts/drug effects,injuries,physiology Receptors, Cell Surface/antagonists & inhibitors,physiology Serotonin Spinal Cord/drug effects,physiology Spinal Cord Injuries/drug therapy
Chemicals
Cornified Envelope Proline-Rich Proteins GPI-Linked Proteins Membrane Proteins Myelin Proteins NEPI-40 protein, mouse Nogo Receptor 1 Peptide Fragments Proteins Receptors, Cell Surface Rtn4r protein, mouse Rtn4r protein, rat Serotonin
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Li Shuxin
Department of Neurology and Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Strittmatter Stephen M
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2003-05-15
Pages
4219-27
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6741116
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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