Original Article

Recovery from chronic spinal cord contusion after nogo receptor intervention

  1. Xingxing Wang1,
  2. Philip Duffy1,
  3. Aaron W. McGee1,2,
  4. Omar Hasan1,
  5. Grahame Gould1,
  6. Nathan Tu1,
  7. Noam Y. Harel1,
  8. Yiyun Huang3,
  9. Richard E. Carson3,
  10. David Weinzimmer3,
  11. Jim Ropchan3,
  12. Larry I. Benowitz4,
  13. William B. J. Cafferty1,
  14. Stephen M. Strittmatter1,*

Article first published online: 7 DEC 2011

DOI: 10.1002/ana.22527

Issue

Annals of Neurology

Annals of Neurology

Volume 70, Issue 5, pages 805–821, November 2011

Additional Information

How to Cite

Wang, X., Duffy, P., McGee, A. W., Hasan, O., Gould, G., Tu, N., Harel, N. Y., Huang, Y., Carson, R. E., Weinzimmer, D., Ropchan, J., Benowitz, L. I., Cafferty, W. B. J. and Strittmatter, S. M. (2011), Recovery from chronic spinal cord contusion after nogo receptor intervention. Ann Neurol., 70: 805–821. doi: 10.1002/ana.22527

Author Information

  1. 1

    Cellular Neuroscience, Neurodegeneration, and Repair Program, and Departments of Neurology and Neurobiology, Yale School of Medicine, New Haven, CT

  2. 2

    Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA

  3. 3

    Positron Emission Tomography Center, Department of Diagnostic Radiology, Yale School of Medicine, New Haven, CT

  4. 4

    Children's Hospital, Harvard Medical School, Boston, MA

*Yale University School of Medicine, Program in Cellular Neuroscience, Neurodegeneration, and Repair, P.O. Box 9812, New Haven, CT 06536-0812

Publication History

  1. Issue published online: 7 DEC 2011
  2. Article first published online: 7 DEC 2011
  3. Accepted manuscript online: 28 JUN 2011 02:22PM EST
  4. Manuscript Accepted: 17 JUN 2011
  5. Manuscript Revised: 1 JUN 2011
  6. Manuscript Received: 29 MAR 2011

Funded by

  • Christopher and Dana Reeve Foundation
  • Wings for Life Foundation
  • Dr Ralph and Marion Falk Medical Research Trust
  • NINDS

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Abstract

Objective:

Several interventions promote axonal growth and functional recovery when initiated shortly after central nervous system injury, including blockade of myelin-derived inhibitors with soluble Nogo receptor (NgR1, RTN4R) decoy protein. We examined the efficacy of this intervention in the much more prevalent and refractory condition of chronic spinal cord injury.

Methods:

We eliminated the NgR1 pathway genetically in mice by conditional gene targeting starting 8 weeks after spinal hemisection injury and monitored locomotion in the open field and by video kinematics over the ensuing 4 months. In a separate pharmacological experiment, intrathecal NgR1 decoy protein administration was initiated 3 months after spinal cord contusion injury. Locomotion and raphespinal axon growth were assessed during 3 months of treatment between 4 and 6 months after contusion injury.

Results:

Conditional deletion of NgR1 in the chronic state results in gradual improvement of motor function accompanied by increased density of raphespinal axons in the caudal spinal cord. In chronic rat spinal contusion, NgR1 decoy treatment from 4 to 6 months after injury results in 29% (10 of 35) of rats recovering weight-bearing status compared to 0% (0 of 29) of control rats (p < 0.05). Open field Basso, Beattie, and Bresnahan locomotor scores showed a significant improvement in the NgR-treated group relative to the control group (p < 0.005, repeated measures analysis of variance). An increase in raphespinal axon density caudal to the injury is detected in NgR1 decoy-treated animals by immunohistology and by positron emission tomography using a serotonin reuptake ligand.

Interpretation:

Antagonizing myelin-derived inhibitors signaling with NgR1 decoy augments recovery from chronic spinal cord injury. ANN NEUROL 2011

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