Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers.

Background: After 30 years of characterisation and implementation, fluid percussion injury (FPI) is firmly recognised as one of the best-characterised reproducible and clinically relevant models of TBI, encompassing concussion through diffuse axonal injury (DAI). Depending on the specific injury parameters (e.g.

Delayed neuromotor recovery and increased memory acquisition dysfunction following experimental brain trauma in mice lacking the DNA repair gene XPA.

Object: This study investigates the outcome after traumatic brain injury (TBI) in mice lacking the essential DNA repair gene xeroderma pigmentosum group A (XPA). As damage to DNA has been implicated in neuronal cell death in various models, the authors sought to elucidate whether the absence of an essential DNA repair factor would affect the outcome of TBI in an experimental setting.

Methods: Thirty-seven adult mice of either wild-type (n = 18) or XPA-deficient ("knock-out" [n = 19]) genotype were subjected to controlled cortical impact experimental brain trauma, which produced a focal brain injury.

Deletion of the p53 tumor suppressor gene improves neuromotor function but does not attenuate regional neuronal cell loss following experimental brain trauma in mice.

Deletion of the tumor suppressor gene p53 has been shown to improve the outcome in experimental models of focal cerebral ischemia and kainate-induced seizures. To evaluate the potential role of p53 in traumatic brain injury, genetically modified mice lacking a functional p53 gene (p53(-/-), n = 9) and their wild-type littermates (p53(+/+), n = 9) were anesthetized and subjected to controlled cortical impact (CCI) experimental brain trauma. After brain injury, neuromotor function was assessed by using composite neuroscore and rotarod tests.

Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients.

Concussive head injury opens a temporary window of brain vulnerability due to the impairment of cellular energetic metabolism. As experimentally demonstrated, a second mild injury occurring during this period can lead to severe brain damage, a condition clinically described as the second impact syndrome. To corroborate the validity of proton magnetic resonance spectroscopy in monitoring cerebral metabolic changes following mild traumatic brain injury, apart from the magnetic field strength (1.

Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice.

Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI.

C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice.

Objective: The aim of the study was to evaluate the effects of C1-inhibitor (C1-INH), an endogenous inhibitor of complement and kinin systems, on neurobehavioral and histological outcome following controlled cortical impact brain injury.

Design: Experimental prospective randomized study in mice.

Setting: Experimental laboratory.

Erythropoietin as a neuroprotective agent in traumatic brain injury Review.

Background: In the United States, TBI remains a major cause of morbidity and mortality in children and young adults. A total of 1.5 million Americans experience head trauma every year, and the yearly economic cost of this exceeds $56 billion.

The use of Hypertonic Saline in the Treatment of Post-Traumatic Cerebral Edema: A Review.

Effective methods for treating cerebral edema have recently become a matter of both extensive research and significant debate within the neurosurgery and trauma surgery communities. The pathophysiologic progression and outcome of different forms of cerebral edema associated with traumatic brain injury have yet to be fully elucidated. There are heterogeneous factors influencing the onset and progress of post-traumatic cerebral edema, including the magnitude and type of head injury, age, co-morbid conditions of the patient, the critical window for therapeutic intervention and the presence of secondary insults including hypoxia, hypotension, hypo/hyperthermia, degree of raised intracranial pressure (ICP), and disruption of blood brain barrier (BBB) integrity.

TrkB gene transfer does not alter hippocampal neuronal loss and cognitive deficits following traumatic brain injury in mice.

Purpose: The ability of brain-derived neurotrophic factor (BDNF) to attenuate secondary damage and influence behavioral outcome after experimental traumatic brain injury (TBI) remains controversial. Because TBI can result in decreased expression of the trkB receptor, thereby preventing BDNF from exerting potential neuroprotective effects, the contribution of both BDNF and its receptor trkB to hippocampal neuronal loss and cognitive dysfunction were evaluated.

Methods: Full-length trkB was overexpressed in the left hippocampus of adult C57Bl/6 mice using recombinant adeno-associated virus serotype 2/5 (rAAV 2/5).

Cognitive outcome following brain injury and treatment with an inhibitor of Nogo-A in association with an attenuated downregulation of hippocampal growth-associated protein-43 expression.

Object: Central nervous system axons regenerate poorly after traumatic brain injury (TBI), partly due to inhibitors such as the protein Nogo-A present in myelin. The authors evaluated the efficacy of anti-Nogo-A monoclonal antibody (mAb) 7B12 administration on the neurobehavioral and cognitive outcome of rats following lateral fluid-percussion brain injury, characterized the penetration of the 7B12 or control antibodies into target brain regions, and evaluated the effects of Nogo-A inhibition on hemispheric tissue loss and sprouting of uninjured motor tracts in the cervical cord. To elucidate a potential molecular response to Nogo-A inhibition, we evaluated the effects of 7B12 on hippocampal GAP-43 expression.

The novel antiepileptic agent RWJ-333369-A, but not its analog RWJ-333369, reduces regional cerebral edema without affecting neurobehavioral outcome or cell death following experimental traumatic brain injury.

Purpose: To evaluate the therapeutic efficacy of two antiepileptic compounds, RWJ-333369 and RWJ-333369-A in a well-established experimental model of lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat.

Methods: Anethestized Male Sprague-Dawley rats (n=227) were subjected to lateral FP brain injury or sham-injury. Animals were randomized to receive treatment with RWJ-333369 (60 mg/kg, p.

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

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).

Thalamic nuclei after human blunt head injury.

Paraffin-embedded blocks from the thalamus of 9 control patients, 9 moderately disabled, 12 severely disabled, and 10 vegetative head-injured patients assessed using the Glasgow Outcome Scale and identified from the Department of Neuropathology archive. Neurons, astrocytes, macrophages, and activated microglia were differentiated by Luxol fast blue/cresyl violet, GFAP, CD68, and CR3/43 staining and stereological techniques used to estimate cell number in a 28-microm-thick coronal section. Counts were made in subnuclei of the mediodorsal, lateral posterior, and ventral posterior nuclei, the intralaminar nuclei, and the related internal lamina.

Evaluation of pharmacological treatment strategies in traumatic brain injury.

Traumatic brain injury (TBI) is a devastating disease, predominately affecting young people. Although the prognosis for TBI victims has improved in recent years, many survivors of TBI suffer from emotional, cognitive and motor disturbances and a decreased quality of life. In recent years, there has been a rapid increase in the number of pharmacological targets evaluated in clinically-relevant experimental TBI models, showing improved cognitive and motor outcome and decreased loss of brain tissue.

Cognitive evaluation of traumatically brain-injured rats using serial testing in the Morris water maze.

Purpose: As deficits in memory and cognition are commonly observed in survivors of traumatic brain injury (TBI), causing reduced quality of life for the patient, a major goal in experimental TBI research is to identify and evaluate cognitive dysfunction. The present study assessed the applicability of the serial Morris water maze (MWM) test to determine cognitive function following experimental TBI in the same group of rats which is particularly important for long-term studies and increasingly valuable for the evaluation of novel treatment strategies.

Methods: Male Sprague-Dawley rats (n = 27) were anesthetized and subjected to either sham injury (n = 9) or lateral fluid percussion (FP) brain injury of moderate severity (n = 18).

Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury.

We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete glial cell line-derived neurotrophic factor (GDNF) to survive, differentiate and promote functional recovery following engraftment into the brains of adult male Sprague-Dawley rats subjected to lateral fluid percussion brain injury. First, we demonstrated continued cortical expression of GDNF receptor components (GFRalpha-1, c-Ret), suggesting that GDNF could have a physiological effect in the immediate post-traumatic period.

Animal models of post-traumatic epilepsy.

Epilepsy is a major unfavorable long-term consequence of traumatic brain injury (TBI). Moreover, TBI is one of the most important predisposing factors for the development of epilepsy, particularly in young adults. Understanding the molecular and cellular cascades that lead to the development of post-traumatic epilepsy (PTE) is key for preventing its development or modifying the disease process in such a way that epilepsy, if it develops, is milder and easier-to-treat.

Activation of Rho after traumatic brain injury and seizure in rats.

Traumatic brain injury (TBI) is characterized by a progressive cell loss and a lack of axonal regeneration. In the central nervous system (CNS), the Rho signaling pathway regulates the neuronal response to growth inhibitory proteins and regeneration of damaged axons, and Rho activation is also correlated with an increased susceptibility to apoptosis. To evaluate whether traumatic brain injury (TBI) results in changes in Rho activation in vulnerable regions of the brain, GTP-RhoA pull down assays were performed on rat cortical and hippocampal tissue homogenates obtained from 24 h to 3 days following lateral fluid percussion brain injury (FPI).

Early, transient increase in complexin I and complexin II in the cerebral cortex following traumatic brain injury is attenuated by N-acetylcysteine.

Alteration of excitatory neurotransmission is a key feature of traumatic brain injury (TBI) in which extracellular glutamate levels rise. Although increased synaptic release of glutamate occurs at the injury site, the precise mechanism is unclear. Complexin I and complexin II constitute a family of cytosolic proteins involved in the regulation of neurotransmitter release, competing with the chaperone protein alpha-SNAP (soluble N-ethylmaleimide-sensitive factor-attachment protein) for binding to the synaptic vesicle protein synaptobrevin as well as the synaptic membrane proteins SNAP-25 and syntaxin, which together form the SNAP receptor (SNARE) complex.

Acute, transient hemorrhagic hypotension does not aggravate structural damage or neurologic motor deficits but delays the long-term cognitive recovery following mild to moderate traumatic brain injury.

Objectives: Posttraumatic hypotension is believed to increase morbidity and mortality in traumatically brain-injured patients. Using a clinically relevant model of combined traumatic brain injury with superimposed hemorrhagic hypotension in rats, the present study evaluated whether a reduction in mean arterial blood pressure aggravates regional brain edema formation, regional cell death, and neurologic motor/cognitive deficits associated with traumatic brain injury.

Design: Experimental prospective, randomized study in rodents.

Stem cell transplantation as a therapeutic strategy for traumatic brain injury.

Stem cell transplantation has enormous potential to be a viable therapeutic approach to replace the lost tissue/cells following traumatic brain injury (TBI). Several types of cell lines such as immortalized progenitors cells, embryonic rodent and human stem cells and bone marrow-derived cells have been successfully transplanted in experimental models of TBI, resulting in reduced neurobehavioral deficits and attenuation of histological damage. To date, it remains unclear whether stem cell are effective following transplantation into the injured brain via either cell replacement, trophic support, or manipulation of the local environment to stimulate endogenous neuroprotection/regeneration.

Delayed transplantation of human neurons following brain injury in rats: a long-term graft survival and behavior study.

The NTera2 (NT2) cell line is a homogeneous population of cells, which, when treated in vitro with retinoic acid, terminally differentiate into postmitotic neuronal NT2N cells. Although NT2N neurons transplanted in the acute (24 h postinjury) period survive for up to 1 month following experimental traumatic brain injury (TBI), nothing is known of their ability to survive for longer periods or of their effects when engrafted during the chronic postinjury period. Adult male Sprague-Dawley rats (n = 348; 360-400 g) were initially anesthetized and subjected to severe lateral fluid-percussion (FP) brain injury or sham injury.

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat.

Axons show a poor regenerative capacity following traumatic central nervous system (CNS) injury, partly due to the expression of inhibitors of axonal outgrowth, of which Nogo-A is considered the most important. We evaluated the acute expression of Nogo-A, the Nogo-66 receptor (NgR) and the novel small proline-rich repeat protein 1A (SPRR1A, previously undetected in brain), following experimental lateral fluid percussion (FP) brain injury in rats. Immunofluorescence with antibodies against Nogo-A, NgR and SPRR1A was combined with antibodies against the neuronal markers NeuN and microtubule-associated protein (MAP)-2 and the oligodendrocyte marker RIP, while Western blot analysis was performed for Nogo-A and NgR.

Caspase-mediated cell death predominates following engraftment of neural progenitor cells into traumatically injured rat brain.

Neural progenitor cells (NPCs) have been shown to be a promising therapy for cell replacement and gene transfer in neurological diseases including traumatic brain injury (TBI). However, NPCs often survive poorly after transplantation despite immunosuppression, and the mechanisms of graft cell death are unknown. In this study, we evaluated caspase- and calpain-mediated mechanisms of cell death of neonatal mouse C17.

Photon correlation spectroscopy of brain mitochondrial populations: application to traumatic brain injury.

Mitochondrial dysfunction and pathology that contribute to a host of neurodegenerative diseases are deduced from changes in ultrastructure, routinely examined by a host of optical techniques. We adapted the technique of photon correlation spectroscopy (PCS) to evaluate calcium-induced structural alterations in isolated viable cortical and hippocampal mitochondria. In detecting calcium-induced reductions in light intensity, PCS was more sensitive than absorbance across varying calcium concentrations.