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

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...

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Published in:	Neuroscience Vol. 134; no. 3; pp. 1047 - 1056
Main Authors:	Lenzlinger, P.M., Shimizu, S., Marklund, N., Thompson, H.J., Schwab, M.E., Saatman, K.E., Hoover, R.C., Bareyre, F.M., Motta, M., Luginbuhl, A., Pape, R., Clouse, A.K., Morganti-Kossmann, C., McIntosh, T.K.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 2005 Elsevier
Subjects:	Analysis of Variance Animals Antibodies - pharmacology Axons - physiology Behavior, Animal Biological and medical sciences Biotin - analogs & derivatives Biotin - metabolism Brain Injuries - physiopathology cognition Cognition - physiology Dextrans - metabolism Disease Models, Animal Functional Laterality Fundamental and applied biological sciences. Psychology head injury hippocampus Hippocampus - pathology Injuries of the nervous system and the skull. Diseases due to physical agents Male Medical sciences Motor Activity - physiology myelin inhibitors Myelin Proteins - immunology Myelin Proteins - physiology Nogo Proteins Rats Rats, Sprague-Dawley Reaction Time Recovery of Function - physiology Time Factors tract-tracing Traumas. Diseases due to physical agents Vertebrates: nervous system and sense organs tract-tracing CNS FP PFA head injury PNS ANOVA NgR TBI PBS MWM OMgp cognition hippocampus DAB CST myelin inhibitors TBST S.E.M TB mAb MAG GAP SCI BDA Nervous system diseases Rat Myelin Craniocerebral Rodentia Central nervous system Cognition Encephalon Vertebrata Mammalia Functional recovery Animal Lesion Head trauma Hippocampus
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2005.04.048