Journal of neurotrauma
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Journal of neurotrauma · Oct 2007
Diffuse brain injury in the immature rat: evidence for an age-at-injury effect on cognitive function and histopathologic damage.
Diffuse axonal injury is a significant component of the pathology of moderate-severe pediatric traumatic brain injury in children less than 4 years of age, and is associated with poor cognitive outcome. However, cognitive deficits or gross histopathologic abnormalities are typically not observed following moderate-severe diffuse brain injury in the immature (17-day-old) rat. In order to test whether the age of the immature animal may influence post-traumatic outcome, non-contusive brain trauma was induced in post-natal day (PND) 11 or 17 rats. ⋯ Quantitative analysis revealed a time-dependent increase in tissue loss in the injured hemisphere (7-10%) in the younger animals, and a modest extent of tissue loss in the older animals (3-4%). Traumatic axonal injury was observed to similar extents in the white matter and thalamus below the impact site in both brain-injured PND11 and 17 rats. These data demonstrate that non-contusive (diffuse) brain injury of moderate severity in the immature rat is associated with chronic cognitive deficits and long-term histopathologic alterations and suggest that the age-at-injury is an important parameter of behavioral and pathologic outcome following closed head injury in the immature age group.
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Journal of neurotrauma · Oct 2007
Post-treatment with the cyclosporin derivative, NIM811, reduced indices of cell death and increased the volume of spared tissue in the acute period following spinal cord contusion.
Cyclosporin A (CsA) is a potent immunosuppressive drug shown to inhibit mitochondrial permeability transition (mPT). Although the therapeutic efficacy of CsA in traumatic brain injury is being investigated, CsA is highly neurotoxic and any neuroprotective effect in models of spinal cord injury (SCI) is unclear. NIM811 is a non-immunosuppressive CsA derivative that inhibits mPT, and is significantly less cytotoxic than CsA. ⋯ NIM811 also reduced the volume of the lesion, and enhanced the volumes of spared gray and white matter at 7 days post-injury. Together, these findings suggest that NIM811 treatment promoted tissue survival following SCI, in part, through inhibition of apoptotic mechanisms. This is the first study to demonstrate the therapeutic potential of NIM811 post-treatment in a model of acute SCI, and supports the need for continued investigation into NIM811 as a neuroprotective treatment for human SCI.
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Journal of neurotrauma · Oct 2007
Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra.
Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1alpha (IL-1alpha) and IL-1beta in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1alpha, IL-1beta, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. ⋯ It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1beta in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.
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Journal of neurotrauma · Sep 2007
Low concentration of isoflurane promotes the development of neurogenic pulmonary edema in spinal cord injured rats.
Anesthetics can either promote or inhibit the development of neurogenic pulmonary edema (NPE) after central nervous system (CNS) injury. The influence of isoflurane was examined in male Wistar rats using 1.5%, 2%, 2.5%, 3%, 4%, or 5% isoflurane in air. Epidural balloon compression of the thoracic spinal cord was performed. ⋯ Animals from the 3% group recovered behaviorally more rapidly than did the animals from the 1.5% group; morphometry and MRI of the lesions showed no differences. Thus, low levels of isoflurane anesthesia promote NPE in rats with a compressed spinal cord and significantly complicates their recovery. The optimal concentration of anesthesia for performing a spinal cord compression lesion is 2.5-3% isoflurane in air.
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Journal of neurotrauma · Sep 2007
Chronic cognitive deficits and long-term histopathological alterations following contusive brain injury in the immature rat.
Although diffuse axonal injury is the primary pathology in pediatric brain trauma, the additional presence of focal contusions may contribute to the poor prognosis in brain-injured children younger than 4 years of age. Because existing models of pediatric brain trauma focus on diffuse brain injury, a model of contusive brain trauma was developed using postnatal day (PND) 11 and 17 rats, ages that are neurologically equivalent to a human infant and toddler, respectively. Closed head injury was modeled by subjecting the intact skull over the left parietal cortex of the immature rat to an impact with a metal-tipped indenter. ⋯ In contrast, in PND17 rats, the contused cortex observed at 3 days post-injury matured into a pronounced cavity lined with a glia limitans at 14 days; reactive astrocytes were present in both the hippocampus and thalamus up to 28 days post-injury. No evidence of traumatic axonal injury was observed in any region of the brain-injured PND17 rat. These data suggest that contusive brain trauma in the immature rat is associated with chronic cognitive deficits, but underscore the effect of the age-at-injury on behavioral and histopathologic outcomes.