Journal of neurotrauma
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Journal of neurotrauma · May 2011
Cyclosporin A preserves mitochondrial function after traumatic brain injury in the immature rat and piglet.
Cyclosporin A (CsA) has been shown to be neuroprotective in mature animal models of traumatic brain injury (TBI), but its effects on immature animal models of TBI are unknown. In mature animal models, CsA inhibits the opening of the mitochondrial permeability transition pore (MPTP), thereby maintaining mitochondrial homeostasis following injury by inhibiting calcium influx and preserving mitochondrial membrane potential. The aim of the present study was to evaluate CsA's ability to preserve mitochondrial bioenergetic function following TBI (as measured by mitochondrial respiration and cerebral microdialysis), in two immature models (focal and diffuse), and in two different species (rat and piglet). ⋯ In piglets, CsA also preserved lactate pyruvate ratios (LPR), as measured by cerebral microdialysis and CBF at sham levels 24 h after injury, in contrast to the significant alterations seen in injured piglets compared to shams (p<0.01). The administration of CsA to piglets following RNR promoted a 42% decrease in injured brain volume (p<0.01). We conclude that CsA exhibits significant neuroprotective activity in immature models of focal and diffuse TBI, and has exciting translational potential as a therapeutic agent for neuroprotection in children.
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Journal of neurotrauma · May 2011
Multicenter StudyA phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury.
Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. ⋯ Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.
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Journal of neurotrauma · May 2011
Early post-traumatic seizures in moderate to severe pediatric traumatic brain injury: rates, risk factors, and clinical features.
We performed a retrospective, observational study at a level I pediatric trauma center of children with moderate-to-severe traumatic brain injury (TBI) from January 2002 to September 2006 to identify clinical and radiographic risk factors for early post-traumatic seizures (EPTS). Two hundred and ninety-nine children ages 0-15 years were evaluated, with 24 excluded because they died before the initial head computed tomography (CT) was obtained (n=20), or because their medical records were missing (n=4). Records were reviewed for accident characteristics, pre-hospital hypoxia or hypotension, initial non-contrast head CT characteristics, seizure occurrence, antiepileptic drug (AED) administration, and outcome. ⋯ AED treatment was protective against EPTS (OR 0.2 [95% CI 0.07,0.5]). Twenty-three (68%) patients developed EPTS within the first 12 h post-injury. This early peak in EPTS activity and demonstrated protective effect of AED administration in this cohort suggests that to evaluate the maximal potential benefit among patients at increased risk for EPTS, future research should be randomized and prospective, and should intervene during pre-trauma center care with initiation of continuous EEG monitoring as soon as possible.
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Journal of neurotrauma · May 2011
Variants of the endothelial nitric oxide gene and cerebral blood flow after severe traumatic brain injury.
Experimental studies suggest that nitric oxide produced by endothelial nitric oxide synthase (NOS3) plays a role in maintaining cerebral blood flow (CBF) after traumatic brain injury (TBI). The purpose of this study was to determine if common variants of the NOS3 gene contribute to hypoperfusion after severe TBI. Fifty-one patients with severe TBI were studied. ⋯ The findings in this study support the importance of NO produced by NOS3 activity in maintaining CBF after TBI, since lower CBF values were found in patients having the -786C allele. The study suggests that a patient's individual genetic makeup may contribute to the brain's response to injury and determine the patient's chances of surviving the injury. The results here will need to be studied in a larger number of patients, but could explain some of the variability in outcome that occurs following severe TBI.
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Journal of neurotrauma · May 2011
Sigma receptor agonist 2-(4-morpholinethyl)1 phenylcyclohexanecarboxylate (Pre084) increases GDNF and BiP expression and promotes neuroprotection after root avulsion injury.
Spinal root avulsion leads to a progressive loss of axotomized motoneurons (MNs). Nowadays, there is no effective treatment to prolong MN survival that could permit recovery as a result of delayed surgical repair. Administration of Sigma-1 receptor (Sig-1R) ligands has been reported to promote beneficial effects after several types of neural injury. ⋯ Moreover, Pre084 produced an increase in the Sig-1R co-chaperone BiP within MNs, and an increase of GDNF expression by astrocytes in the ventral horn early after injury. Although the mechanisms promoting MN survival by Pre084 remain unclear, we hypothesize that it is mediated at least in part through the increase in these cytoprotective factors. Therefore, early application of Sig-1R agonist appears to be a promising therapy to improve MN survival after root avulsion.