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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 staining and hippocampal β-amyloid (Aβ) 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 Aβ 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. [Copyright &y& Elsevier]

Abstract: Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]