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Tissue sparing and functional recovery following experimental traumatic brain injury is provided by treatment with an anti-myelin-associated glycoprotein antibody

Thompson, Hilaire J; Marklund, Niklas LU ; LeBold, David G; Morales, Diego M; Keck, Carrie A; Vinson, Mary; Royo, Nicolas C; Grundy, Robert and McIntosh, Tracy K (2006) In European Journal of Neuroscience 24(11). p.72-3063
Abstract

Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n=102) were subjected to either lateral fluid percussion brain injury (n=59) or sham injury (n=43). In surviving animals, beginning at 1 h post-injury, 8.64 microg anti-MAG mAb (n=33 injured, n=21 sham) or... (More)

Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n=102) were subjected to either lateral fluid percussion brain injury (n=59) or sham injury (n=43). In surviving animals, beginning at 1 h post-injury, 8.64 microg anti-MAG mAb (n=33 injured, n=21 sham) or control IgG (n=26 injured, n=22 sham) was infused intracerebroventricularly for 72 h. One group of these rats (n=14 sham, n=11 injured) was killed at 72 h post-injury for verification of drug diffusion and MAG immunohistochemistry. All other animals were evaluated up to 8 weeks post-injury using tests for neurologic motor, sensory and cognitive function. Hemispheric tissue loss was also evaluated at 8 weeks post-injury. At 72 h post-injury, increased immunoreactivity for MAG was seen in the ipsilateral cortex, thalamus and hippocampus of brain-injured animals, and anti-MAG mAb was detectable in the hippocampus, fimbria and ventricles. Brain-injured animals receiving anti-MAG mAb showed significantly improved recovery of sensorimotor function at 6 and 8 weeks (P<0.01) post-injury when compared with brain-injured IgG-treated animals. Additionally, at 8 weeks post-injury, the anti-MAG mAb-treated brain-injured animals demonstrated significantly improved cognitive function and reduced hemispheric tissue loss (P<0.05) when compared with their brain-injured controls. These results indicate that MAG may contribute to the pathophysiology of experimental TBI and treatment strategies that target MAG may be suitable for further evaluation.

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publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Antibodies, Monoclonal, Axons, Brain, Brain Injuries, Demyelinating Diseases, Disease Models, Animal, Immunohistochemistry, Male, Myelin-Associated Glycoprotein, Nerve Regeneration, Rats, Rats, Sprague-Dawley, Recovery of Function, Treatment Outcome, Wallerian Degeneration, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
in
European Journal of Neuroscience
volume
24
issue
11
pages
10 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:33845676295
ISSN
0953-816X
DOI
10.1111/j.1460-9568.2006.05197.x
language
English
LU publication?
no
id
d7b9df03-3de4-45c5-94db-96c91e835c38
date added to LUP
2016-12-08 12:20:37
date last changed
2019-10-23 05:05:41
@article{d7b9df03-3de4-45c5-94db-96c91e835c38,
  abstract     = {<p>Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n=102) were subjected to either lateral fluid percussion brain injury (n=59) or sham injury (n=43). In surviving animals, beginning at 1 h post-injury, 8.64 microg anti-MAG mAb (n=33 injured, n=21 sham) or control IgG (n=26 injured, n=22 sham) was infused intracerebroventricularly for 72 h. One group of these rats (n=14 sham, n=11 injured) was killed at 72 h post-injury for verification of drug diffusion and MAG immunohistochemistry. All other animals were evaluated up to 8 weeks post-injury using tests for neurologic motor, sensory and cognitive function. Hemispheric tissue loss was also evaluated at 8 weeks post-injury. At 72 h post-injury, increased immunoreactivity for MAG was seen in the ipsilateral cortex, thalamus and hippocampus of brain-injured animals, and anti-MAG mAb was detectable in the hippocampus, fimbria and ventricles. Brain-injured animals receiving anti-MAG mAb showed significantly improved recovery of sensorimotor function at 6 and 8 weeks (P&lt;0.01) post-injury when compared with brain-injured IgG-treated animals. Additionally, at 8 weeks post-injury, the anti-MAG mAb-treated brain-injured animals demonstrated significantly improved cognitive function and reduced hemispheric tissue loss (P&lt;0.05) when compared with their brain-injured controls. These results indicate that MAG may contribute to the pathophysiology of experimental TBI and treatment strategies that target MAG may be suitable for further evaluation.</p>},
  author       = {Thompson, Hilaire J and Marklund, Niklas and LeBold, David G and Morales, Diego M and Keck, Carrie A and Vinson, Mary and Royo, Nicolas C and Grundy, Robert and McIntosh, Tracy K},
  issn         = {0953-816X},
  keyword      = {Animals,Antibodies, Monoclonal,Axons,Brain,Brain Injuries,Demyelinating Diseases,Disease Models, Animal,Immunohistochemistry,Male,Myelin-Associated Glycoprotein,Nerve Regeneration,Rats,Rats, Sprague-Dawley,Recovery of Function,Treatment Outcome,Wallerian Degeneration,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't,Research Support, U.S. Gov't, Non-P.H.S.},
  language     = {eng},
  number       = {11},
  pages        = {72--3063},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Neuroscience},
  title        = {Tissue sparing and functional recovery following experimental traumatic brain injury is provided by treatment with an anti-myelin-associated glycoprotein antibody},
  url          = {http://dx.doi.org/10.1111/j.1460-9568.2006.05197.x},
  volume       = {24},
  year         = {2006},
}