Delayed inhibition of Nogo-A does not alter injury-induced axonal sprouting but enhances recovery of cognitive function following experimental traumatic brain injury in rats

P. M. Lenzlinger, S. Shimizu, N. Marklund, H. J. Thompson, M. E. Schwab, K. E. Saatman, R. C. Hoover, F. M. Bareyre, M. Motta, A. Luginbuhl, R. Pape, A. K. Clouse, C. Morganti-Kossmann, T. K. McIntosh

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Traumatic brain injury causes long-term neurological motor and cognitive deficits, often with limited recovery. The inability of CNS axons to regenerate following traumatic brain injury may be due, in part, to inhibitory molecules associated with myelin. One of these myelin-associated proteins, Nogo-A, inhibits neurite outgrowth in vitro, and inhibition of Nogo-A in vivo enhances axonal outgrowth and sprouting and improves outcome following experimental CNS insults. However, the involvement of Nogo-A in the neurobehavioral deficits observed in experimental traumatic brain injury remains unknown and was evaluated in the present study using the 11C7 monoclonal antibody against Nogo-A. Anesthetized, male Sprague-Dawley rats were subjected to either lateral fluid percussion brain injury of moderate severity (2.5-2.6 atm) or sham injury. Beginning 24 h post-injury, monoclonal antibody 11C7 (n=17 injured, n=6 shams included) or control Ab (IgG) (n=16 injured, n=5 shams included) was infused at a rate of 5μl/h over 14 days into the ipsilateral ventricle using osmotic minipumps connected to an implanted cannula. Rats were assessed up to 4 weeks post-injury using tests for neurological motor function (composite neuroscore, and sensorimotor test of adhesive paper removal) and, at 4 weeks, cognition was assessed using the Morris water maze. Hippocampal CA3 pyramidal neuron damage and corticospinal tract sprouting, using an anterograde tracer (biotinylated dextran amine), were also evaluated. Brain injury significantly increased sprouting from the uninjured corticospinal tract but treatment with monoclonal antibody 11C7 did not further increase the extent of sprouting nor did it alter the extent of CA3 cell damage. Animals treated with 11C7 showed no improvement in neurologic motor deficits but did show significantly improved cognitive function at 4 weeks post-injury when compared with brain-injured, IgG-treated animals. To our knowledge, the present findings are the first to suggest that (1) traumatic brain injury induces axonal sprouting in the corticospinal tract and this sprouting may be independent of myelin-associated inhibitory factors and (2) that post-traumatic inhibition of Nogo-A may promote cognitive recovery unrelated to sprouting in the corticospinal tract or neuroprotective effects on hippocampal cell loss following experimental traumatic brain injury.

Original languageEnglish
Pages (from-to)1047-1056
Number of pages10
Issue number3
StatePublished - 2005

Bibliographical note

Funding Information:
This study was supported by NIH RO1-NS 40978, NS P50-08803, and GM RO1-34690, and a Merit Review Grant from the Veterans Administration. Vehicle IgG and 11C7 antibodies were generously provided by Novartis, Inc., Basel, Switzerland. Dr. Lenzlinger was supported, in part, by a NIH training grant T32 NS07413-04 and a Research Fellowship by the Swiss National Science Foundation (SNF). We thank Mrs. Jeanne Marks for preparation of the manuscript.


  • Cognition
  • Head injury
  • Hippocampus
  • Myelin inhibitors
  • Tract-tracing

ASJC Scopus subject areas

  • General Neuroscience


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