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Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice

Marklund, N LU ; Morales, D; Clausen, F; Hånell, A; Kiwanuka, O; Pitkänen, A; Gimbel, D A; Philipson, O; Lannfelt, L and Hillered, L, et al. (2009) In Neuroscience 163(2). p.51-540
Abstract

Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous(-/-) mice), Nogo-A/B heterozygous(-/+) mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin... (More)

Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous(-/-) mice), Nogo-A/B heterozygous(-/+) mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal beta-amyloid (A beta) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B(-/-) mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B(-/-) mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased A beta expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B(-/-) animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.

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Aging, Amyloid beta-Peptides, Animals, Brain Injuries, Cognition Disorders, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelin Proteins, Myelin Sheath, Neuropsychological Tests, Organ Size, Random Allocation, Recovery of Function, Time Factors, Treatment Outcome, 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.
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Neuroscience
volume
163
issue
2
pages
12 pages
publisher
Elsevier
external identifiers
  • scopus:69249222650
ISSN
1873-7544
DOI
10.1016/j.neuroscience.2009.06.042
language
English
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0d8e90c3-f685-43c0-be95-599913993f0d
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@article{0d8e90c3-f685-43c0-be95-599913993f0d,
  abstract     = {<p>Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous(-/-) mice), Nogo-A/B heterozygous(-/+) mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal beta-amyloid (A beta) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B(-/-) mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B(-/-) mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased A beta expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B(-/-) animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.</p>},
  author       = {Marklund, N and Morales, D and Clausen, F and Hånell, A and Kiwanuka, O and Pitkänen, A and Gimbel, D A and Philipson, O and Lannfelt, L and Hillered, L and Strittmatter, S M and McIntosh, T K},
  issn         = {1873-7544},
  keyword      = {Aging,Amyloid beta-Peptides,Animals,Brain Injuries,Cognition Disorders,Female,Male,Mice,Mice, Inbred C57BL,Mice, Knockout,Myelin Proteins,Myelin Sheath,Neuropsychological Tests,Organ Size,Random Allocation,Recovery of Function,Time Factors,Treatment Outcome,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},
  month        = {10},
  number       = {2},
  pages        = {51--540},
  publisher    = {Elsevier},
  series       = {Neuroscience},
  title        = {Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice},
  url          = {http://dx.doi.org/10.1016/j.neuroscience.2009.06.042},
  volume       = {163},
  year         = {2009},
}