Post-injury Days Research Articles

Endocrine function in children acutely following severe traumatic brain injury

Despite the prevalence of frontal injury following traumatic brain injury (TBI) in adults and children with potentially concomitant hypothalamic and pituitary involvement, endocrine dysfunction acutely following TBI has not been well studied in children. To study the acute pediatric endocrine response after severe TBI (Glasgow Coma Scale <or= 8), an endocrine panel, including cortisol, ACTH, TSH, T3, T4, free T4, GH, and prolactin levels, were obtained in 37 children (1-17 years) on the day of injury and post-injury days (PID) 3 and 7. Outcome was determined at 6-month follow-up using the Glasgow Outcome Score (GOS) extended modified for pediatric patients (GOS-E Peds) to compare "good" (GOS-E Peds 1-2) to "poor" (GOS-E Peds 3-5) outcomes. Our results showed that following severe TBI in children, cortisol was significantly elevated (24.46 +/- 13.41 microg/dL) on PID 1 along with ACTH but then returned to normal (10.14-19.92 microg/dL) by PID 3; 46% and 14% of children had a low cortisol and ACTH (<10.14 and <2, respectively) in the acute period. In summary, the cortisol response to trauma and stress in the acute period following severe TBI in the majority of children was altered, though seemingly appropriate cortisol was abnormally low in a significant percentage of children. Further study as to the significance of these findings is needed, but this study provides preliminary insight into the potential impact of severe TBI on the acute response of the hypothalamic-pituitary axis in children.

Time course for autoregulation recovery following severe traumatic brain injury

The aim of the present study was to evaluate the time course for cerebral autoregulation (AR) recovery following severe traumatic brain injury (TBI). Thirty-six patients (27 males and 9 females, mean +/- SEM age 33 +/- 15.1 years) with severe TBI underwent serial dynamic AR studies with leg cuff deflation as a stimulus, until recovery of the AR responses was measured. The AR was impaired (AR index < 2.8) in 30 (83%) of 36 patients on Days 3-5 after injury, and in 19 individuals (53%) impairments were found on Days 9-11 after the injury. Nine (25%) of 36 patients exhibited a poor AR response (AR index < 1) on postinjury Days 12-14, which eventually recovered on Days 15-23. Fifty-eight percent of the patients with a Glasgow Coma Scale score of 3-5, 50% of those with diffuse brain injury, 54% of those with elevated intracranial pressure, and 40% of those with poor outcome had no AR recovery in the first 11 days after injury. Autoregulation recovery after severe TBI can be delayed, and failure to recover during the 2nd week after injury occurs mainly in patients with a lower Glasgow Coma Scale score, diffuse brain injury, elevated ICP, or unfavorable outcome. The finding suggests that perfusion pressure management should be considered in some of the patients for a period of at least 2 weeks.

Neutralization of interleukin‐1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice

Interleukin-1beta (IL-1beta) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post-injury, the IL-1beta neutralizing antibody IgG2a/k (1.5 microg/mL) or control antibody was infused at a rate of 0.25 microL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T-cell infiltration and microglial activation was evaluated at days 1-7 post-injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post-injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL-1betain vitro. IL-1beta neutralization attenuated the CCI-induced cortical and hippocampal microglial activation (P < 0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils (P < 0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1beta neutralization (P < 0.05 at post-injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue (P < 0.05). In brain-injured animals, IL-1beta neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits (P < 0.05) without influencing neurological motor function. Our results indicate that IL-1beta is a central component in the post-injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.

Evaluating regional blood spinal cord barrier dysfunction following spinal cord injury using longitudinal dynamic contrast-enhanced MRI

BackgroundIn vivo preclinical imaging of spinal cord injury (SCI) in rodent models provides clinically relevant information in translational research. This paper uses multimodal magnetic resonance imaging (MRI) to investigate neurovascular pathology and changes in blood spinal cord barrier (BSCB) permeability following SCI in a mouse model of SCI.MethodsC57BL/6 female mice (n = 5) were subjected to contusive injury at the thoracic T11 level and scanned on post injury days 1 and 3 using anatomical, dynamic contrast-enhanced (DCE-MRI) and diffusion tensor imaging (DTI). The injured cords were evaluated postmortem with histopathological stains specific to neurovascular changes. A computational model was implemented to map local changes in barrier function from the contrast enhancement. The area and volume of spinal cord tissue with dysfunctional barrier were determined using semi-automatic segmentation.ResultsQuantitative maps derived from the acquired DCE-MRI data depicted the degree of BSCB permeability variations in injured spinal cords. At the injury sites, the damaged barriers occupied about 70% of the total cross section and 48% of the total volume on day 1, but the corresponding measurements were reduced to 55% and 25%, respectively on day 3. These changes implied spatio-temporal remodeling of microvasculature and its architecture in injured SC. Diffusion computations included longitudinal and transverse diffusivities and fractional anisotropy index. Comparison of permeability and diffusion measurements indicated regions of injured cords with dysfunctional barriers had structural changes in the form of greater axonal loss and demyelination, as supported by histopathologic assessments.ConclusionThe results from this study collectively demonstrated the feasibility of quantitatively mapping regional BSCB dysfunction in injured cord in mouse and obtaining complementary information about its structural integrity using in vivo DCE-MRI and DTI protocols. This capability is expected to play an important role in characterizing the neurovascular changes and reorganization following SCI in longitudinal preclinical experiments, but with potential clinical implications.

Extracellular matrix gene expression during wound healing of the injured rat vocal fold

Objectives To measure the expression of procollagen-I and -III, decorin, and hyaluronan synthase (HAS)-1, -2, and -3 during the inflammatory, proliferative, and remodeling phases of rat vocal fold injury. Study Design Prospective, animal model. Subjects and Methods Vocal folds were injured in 30 rats. Injured specimens were harvested on postinjury days 1, 3, 7, 14, 28, and 56. Five uninjured rats were used for polymerase chain reaction (PCR) control. Real-time PCR was used to measure the expression of procollagen-I and -III, decorin, and hyaluronan synthase (HAS)-1, -2, and -3. Results Compared with control, expression of procollagen-I and -III were significantly decreased on postinjury days 1 and 56; decorin expression was significantly decreased on postinjury days 1, 3, 7, and 56; HAS-1 expression was significantly decreased on postinjury days 3, 7, 14, 28, and 56; HAS-2 expression was significantly decreased on postinjury days 28 and 56; HAS-3 expression was significantly decreased on postinjury day 56. Conclusions Results revealed time-dependent alterations in the expression of genes coding procollagen-I and -III, decorin, and HAS-1, -2, and -3. Knowledge of the temporal regulation of these genes and underlying histology will be used in future studies to investigate molecular approaches for manipulation of vocal fold injury.

Glucocorticoids Aggravate Retrograde Memory Deficiency Associated with Traumatic Brain Injury in Rats

Administration of glucocorticoid to patients with head injury has previously been demonstrated to impair memory. We hypothesize that glucocorticoids promote post-traumatic hippocampal apoptosis, resulting in retrograde memory deficiency associated with traumatic brain injury (TBI). In the present study, we tested this hypothesis by measuring spatial memory deficiency in rats subjected to fluid percussion injury (FPI) and receiving dexamethasone (DXM at 0.5-10 mg/kg) or methylprednisolone (MP at 5-30 mg/kg); we also examined neuronal apoptosis in hippocampus. Adult male Wistar rats were trained for the acquisition of spatial memory, then subjected to FPI and tested for spatial reference memory on post-injury days 7 and 14 using the Morris Water Maze. Brain tissue from injured rats was examined 24 h to 2 weeks after injury. The percent time in the goal quadrant, which measures spatial reference memory, was significantly lower in injured rats receiving either high-dose DXM or MP than in control groups. TUNEL-positive cells in hippocampus were first detected 24 h post-injury, plateauing at 48h. The number of TUNEL-positive cells was significantly higher in injured rats treated with either DXM or MP. The data suggest that glucocorticoid therapy for TBI may increase neuronal apoptosis in hippocampus and, as a result, aggravate retrograde memory deficits induced by TBI.

The Nitrone Free Radical Scavenger NXY-059 Is Neuroprotective when Administered after Traumatic Brain Injury in the Rat

Reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI. NXY-059, a nitrone free radical trapping compound, has been shown to be neuroprotective in models of ischemic stroke but has not been evaluated in experimental TBI. In the present study, a continuous 24-h intravenous infusion of NXY-059 or vehicle was initiated 30 min following a severe lateral fluid percussion brain injury (FPI) in adult rats (n=22), and histological and behavioral outcomes were evaluated. Sham-injured animals (n=22) receiving identical drug infusion were used as controls. Visuospatial learning was evaluated in the Morris water maze at post-injury days 11-14, followed by a probe trial (memory test) at day 18. The animals were sacrificed at day 18, and loss of hemispheric brain tissue was measured in microtubule-associated protein (MAP)-2 stained sections. Brain-injured, NXY-059-treated animals showed a significant reduction of visuospatial learning deficits when compared to the brain-injured, vehicle-treated control animals (p < 0.05). NXY-059-treated animals significantly reduced the loss of hemispheric tissue compared to brain-injured controls (43.0 +/- 11 mm3 versus 74.4 +/- 19 mm3, respectively; p < 0.01). The results show that post-injury treatment with NXY-059 significantly attenuated the loss of injured brain tissue and improved cognitive outcome, suggesting a major role for ROS in the pathophysiology of TBI.

Hypertonic Resuscitation Improves Neuronal and Behavioral Outcomes after Traumatic Brain Injury plus Hemorrhage

: Resuscitation with hypertonic saline or hypertonic saline plus l-arginine acutely improves cerebral blood flow after traumatic brain injury (TBI) followed by hemorrhagic hypotension. The authors investigated whether hypertonic saline or hypertonic l-arginine would improve long-term neuronal survival and behavioral outcomes 15 days after TBI and hemorrhagic hypotension. : Mean arterial pressure, arterial blood gases, pH, plasma glucose, hematocrit, and hemoglobin were measured in male Sprague-Dawley rats before and after moderate (2.0 atm) fluid percussion TBI. Rats were assigned to one of six groups: (1) sham TBI, (2) hemorrhage only, (3) TBI only, (4) TBI plus hemorrhage and resuscitation with 0.9% saline, (5) TBI plus hemorrhage and resuscitation with hypertonic saline (7.5%), or (6) TBI plus hemorrhage and resuscitation with l-arginine (100 mg/kg) in hypertonic saline. On postinjury days 1-5, vestibulomotor function was assessed using beam balance and beam walking tasks. On postinjury days 11-15, spatial memory function was assessed using the Morris water maze. After behavioral testing, neuronal counting was performed bilaterally on specific hippocampal regions. : Groups receiving hypertonic saline (P < 0.05, day 15 vs. day 11) or hypertonic l-arginine (P < 0.05, days 13-15 vs. day 11) showed improved performance over time on the Morris water maze, as well as significantly improved neuronal survival in the contralateral hippocampus (P < 0.05, hypertonic saline or hypertonic l-arginine vs. normal saline) compared with untreated TBI or normal saline-treated TBI plus hemorrhage groups. : Hypertonic saline and hypertonic l-arginine were both effective at promoting long-term neuronal survival and behavioral recovery. The slightly earlier improvement in Morris water maze performance in the hypertonic l-arginine group warrants further studies to determine whether higher doses of l-arginine provide additional improvement. This study supports the therapeutic benefits of hypertonic resuscitation after TBI plus hemorrhagic hypotension.

Neuronal and Vascular Biomarkers in Syringomyelia: Investigations Using Longitudinal Mri

Syringomyelia is a formation of fluid-filled cavities in the spinal cord, caused by a number of situations including trauma. To understand the origin and progression of syringomyelia, animal models were developed to mimick the condition and computer models were implemented for performing numerical analysis. This article characterizes the neuropathological stages of a contused spinal cord before and after the syringomyelia formation using longitudinal in vivo MRI. Rat was subject to a contusion-type spinal cord injury (SCI) at the T12 level. MRI data were gathered on post-injury days 3, 14, 28, 72, 94 and 404 using a 9.4 T scanner. In addition, neurobehavioral tests were performed prior to the scans on these days. Pathological consequences of SCI included significant edema and, to a lesser degree, hemorrhage in the acute phase, followed by neuronal loss, tissue alterations and vascular changes in the late stages. The images from the post-injury day 14 indicated shrinkage of the injured tissue and occlusion of the central canal. Subsequently, syringomyelia was initiated cranial to the occlusion and the fluid-filled cavities enlarged with time. The neurologic deficits of the injured rat also worsened over time. The inflammatory, but not the hemostatic, component seems to be a prerequisite for syringomyelia proceeding contusive SCI and abnormal flow of the cerebrospinal fluid (CSF) is likely the main factor. Bioimaging markers from high-resolution MRI sensitized to inflammation and CSF flow may be used for early detection of syringomyelia and assessing its prognosis.

Delayed glucose treatment improves cognitive function following fluid-percussion injury

Experimental traumatic brain injury (TBI) results in marked neurochemical and metabolic changes. Research has demonstrated that after the initial insult the brain undergoes an immediate state of hypermetabolism followed by a sustained period of hypometabolism. The altered extra- and intracellular environment can compromise neuronal performance and limit functional recovery. If brain metabolism is depressed chronically after TBI, then interventions that are designed to increase metabolism may be beneficial to outcome. Glucose treatment has been shown to improve cognition in many populations, particularly those with cognitive deficits. The following experiments examined the effects of delayed postinjury glucose supplementation on cognitive function following TBI. Male Sprague-Dawley rats received either sham or lateral fluid-percussion (LFP) injury. Cognitive functioning was assessed with the Morris water maze (MWM) on postinjury days 11-15. In the first experiment, saline or 100mg/kg glucose was administered 10 min before cognition assessment. Injured animals treated with glucose displayed significantly shorter latencies to reach the goal platform compared to injured saline-treated animals. Glucose had no effect on sham-injured rats. In the second experiment, injured rats were given daily injections of saline or 100mg/kg glucose for 10 days beginning 24h after injury. Rats were then tested in the MWM on days 11-15 without glucose or saline treatment. In this experiment, glucose treatment did not affect MWM performance. These data provide evidence that the chronic energy supplementation after TBI improves outcome when administered shortly before cognitive assessment.

Post-Injury Atomoxetine Treatment Improves Cognition following Experimental Traumatic Brain Injury

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-traumatic brain injury (TBI) pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The current study was designed to test the efficacy of atomoxetine in treating cognitive deficits following experimental TBI in animals and to determine an optimal dose and therapeutic window for drug treatment. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- 0.05). Two experiments were performed. In the first study, atomoxetine (0.3, 1, 3, or 9 mg/kg) or vehicle was administered daily on post-injury days (PID) 1-15. Cognitive assessment was performed using the Morris water maze on PID 11-15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine (0.3, 1, and 3 mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9 mg/kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/kg atomoxetine. In the second study, treatment with atomoxetine (1 mg/kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days, and cognitive assessment was performed on PID 25-29. In this study, treatment with atomoxetine (1 mg/kg) did not result in improved cognitive performance. In conclusion, this is the first study to show low-dose atomoxetine initiated early after experimental TBI results in improved cognition.

Effects of Red Deer Antlers on Cutaneous Wound Healing in Full-thickness Rat Models

The process of wound repair involves an ordered sequence of events such as overlapping biochemical and cellular events that, in the best of circumstances, result in the restoration of both the structural and functional integrity of the damaged tissue. An important event during wound healing is the contraction of newly formed connective tissues by fibroblasts. The polypeptide growth factors, like transforming growth factor-β (TGF-β), insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF), play very important mediator roles in the process of wound contraction. Deer antlers, as models of mammalian regeneration, are cranial appendages that develop after birth as extensions of a permanent protuberance (pedicle) on the frontal bone. Antlers contain various growth factors which stimulate dermal fibroblast growth. They are involved in digestion and respiration and are necessary for normal wound healing and skin health. In order to investigate and evaluate the effects of red deer antlers on skin wound site, the speed of full-thickness skin wound healing and the expression of IGF-I, TGF-β, and EGF in skin wounds, three groups of skin full-thickness rat models with a high concentration of antler ointment, a low concentration of antler ointment and without antler ointment were compared. At post-injury days 0, 2, 4, 8, 16, 20, 32, 40 and 60, the skin wound area was measured, the expressions of IGF-I, TGF-β, and EGF mRNA were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and collagen formation by sirius red dye and the localization of IGF-I, TGF-β, and EGF peptides were inspected by histological immunohistochemical techniques. Wound healing was significantly more rapid in antler treated skins. In addition, the wound treated with a high concentration antler ointment, a low concentration antler ointment, and the control closed completely at post-injury day 40, day 44 and day 60, respectively. Via RT-PCR, the expressions of IGF-I (day 8 and day 16), TGF-β (day 8, day 16 and day 20) and EGF (day 4, day 8, day 16, and day 32) were obviously up-regulated in high concentration antler-treated skins compared to control skins. Similar results could be seen in the histological detection of collagen dye and immunohistochemical methods using the corresponding polyclone antibodies of IGF-I, TGF-β, and EGF. These results illustrate that antlers stimulate and accelerate the repair of cutaneous wounds.

Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate‐induced injury is lost by middle age

A remarkable up-regulation of neurogenesis through increased proliferation of neural stem/progenitor cells (NSCs) is a well-known plasticity displayed by the young dentate gyrus (DG) following brain injury. To ascertain whether this plasticity is preserved during aging, we quantified DG neurogenesis in the young adult, middle-aged and aged F344 rats after kainic acid induced hippocampal injury. Measurement of new cells that are added to the dentate granule cell layer (GCL) between post-injury days 4 and 15 using 5'-bromodeoxyuridine labeling revealed an increased addition of new cells in the young DG but not in the middle-aged and aged DG. Quantification of newly born neurons using doublecortin immunostaining also demonstrated a similar trend. Furthermore, the extent of ectopic migration of new neurons into the dentate hilus was dramatically increased in the young DG but was unaltered in the middle-aged and aged DG. However, there was no change in neuronal fate-choice decision of newly born cells following injury in all age groups. Similarly, comparable fractions of new cells that are added to the GCL after injury exhibited 5-month survival and expressed the mature neuronal marker NeuN, regardless of age or injury at the time of their birth. Thus, hippocampal injury does not adequately stimulate NSCs in the middle-aged and aged DG, resulting in no changes in neurogenesis after injury. Interestingly, rates of both neuronal fate-choice decision and long-term survival of newly born cells remain stable with injury in all age groups. These results underscore that the ability of the DG to increase neurogenesis after injury is lost as early as middle age.

Environmental enrichment-mediated functional improvement after experimental traumatic brain injury is contingent on task-specific neurobehavioral experience

Environmental enrichment (EE) is superior to standard (STD) housing in promoting functional recovery after traumatic brain injury (TBI). However, whether the EE-mediated benefits after TBI are dependent on exposure to enrichment during neurobehavioral training has not been elucidated. To address this issue, isoflurane-anesthetized adult male rats received either a cortical impact or sham injury and were then randomly assigned to early EE, delayed EE, continuous EE or no EE (i.e., STD conditions). Continuous EE or no EE was initiated immediately after surgery and continued for the duration of the study. Early EE began directly after surgery, continued for 1 week, and was then followed by STD living (2 rats per cage) for the remainder of the study, while delayed EE commenced 1 week after early STD housing. Functional outcome was assessed with established motor and cognitive tests on post-injury days 1–5 and 14–18, respectively. CA1/CA3 neurons were quantified at 3 weeks. CA3 cell loss was significantly attenuated in the TBI+continuous EE group versus the TBI+no EE group. Beam-walking was facilitated in the TBI groups that received either early or continuous EE versus those receiving delayed or no EE. Cognitive training was enhanced in the TBI groups that received continuous or delayed EE versus the early EE or no EE groups. These data suggest that EE-mediated functional improvement after TBI is contingent on task-specific neurobehavioral experience.

Intensive Insulin Protocol Improves Glucose Control and Is Associated with a Reduction in Intensive Care Unit Mortality

Intensive insulin therapy to maintain serum glucose levels between 80 and 110 mg/dL has previously been shown to reduce mortality in the critically ill; recent data, however, have called this benefit into question. In addition, maintaining uniform, tight glucose control is challenging and resource demanding. We hypothesized that, by use of a protocol, tight glucose control could be achieved in the surgical trauma intensive care unit (STICU), and that improved glucose control would be beneficial. During the study period, a progressively more rigorous approach to glucose control was used, culminating in an implemented protocol in 2005. We reviewed STICU patients' blood glucose levels, measured by point-of-care testing, from 2003 to 2006. Mortality was tracked over the course of the study, and patient charts were retrospectively reviewed to measure illness and injury severity. Mean blood glucose levels steadily improved (p < 0.01). In addition to absolute improvements in glucose control, total variability of glucose ranges in the STICU steadily diminished. A reduction in STICU mortality was temporally associated with implementation of the protocol (p < 0.01). There were fewer intraabdominal abscesses and fewer postinjury ventilator days after implementation of the protocol. There was a small increase in the incidence of clinically relevant hypoglycemia. Improvements in glucose control in the ICU can be achieved by using a protocol for intensive insulin therapy. In our ICU, this was temporally associated with a significant reduction in mortality.

Acute treatment with the 5-HT 1A receptor agonist 8-OH-DPAT and chronic environmental enrichment confer neurobehavioral benefit after experimental brain trauma

Acute treatment with the 5-HT 1A receptor agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) or chronic environmental enrichment (EE) hasten behavioral recovery after experimental traumatic brain injury (TBI). The aim of this study was to determine if combining these interventions would confer additional benefit. Anesthetized adult male rats received either a cortical impact or sham injury followed 15 min later by a single intraperitoneal injection of 8-OH-DPAT (0.5 mg/kg) or saline vehicle (1.0 mL/kg) and then randomly assigned to either enriched or standard (STD) housing. Behavioral assessments were conducted utilizing established motor and cognitive tests on post-injury days 1–5 and 14–18, respectively. Hippocampal CA 1/CA 3 neurons were quantified at 3 weeks. Both 8-OH-DPAT and EE attenuated CA 3 cell loss. 8-OH-DPAT enhanced spatial learning in a Morris water maze (MWM) as revealed by differences between the TBI + 8-OH-DPAT + STD and TBI + VEHICLE + STD groups ( P = 0.0014). EE improved motor function as demonstrated by reduced time to traverse an elevated narrow beam in both the TBI + 8-OH-DPAT + EE and TBI + VEHICLE + EE groups versus the TBI + VEHICLE + STD group ( P = 0.0007 and 0.0016, respectively). EE also facilitated MWM learning as evidenced by both the TBI + 8-OH-DPAT + EE and TBI + VEHICLE + EE groups locating the escape platform quicker than the TBI + VEHICLE + STD group ( P's < 0.0001). MWM differences were also observed between the TBI + 8-OH-DPAT + EE and TBI + 8-OH-DPAT + STD groups ( P = 0.0004) suggesting that EE enhanced the effect of 8-OH-DPAT. However, there was no difference between the TBI + 8-OH-DPAT + EE and TBI + VEHICLE + EE groups. These data replicate previous results from our laboratory showing that both a single systemic administration of 8-OH-DPAT and EE improve recovery after TBI and extend those findings by elucidating that the combination of treatments in this particular paradigm did not confer additional benefit. One explanation for the lack of an additive effect is that EE is a very effective treatment and thus there is very little room for 8-OH-DPAT to confer additional statistically significant improvement.

Longitudinal magnetic resonance imaging of spinal cord injury in mouse: changes in signal patterns associated with the inflammatory response

Contusion-type spinal cord injury (SCI) in mice was followed longitudinally using in vivo magnetic resonance (MR) imaging along with neurobehavioral tests performed on postinjury Days 1, 7, 14 and 28. Magnetic resonance images were acquired from seven injured wild-type mice using a 9.4-T scanner and presented in sagittal and axial views to reflect the current state of the injured cord neuropathology on each day. The data were analyzed individually to gain more insights on the neuroinflammatory response unique to the mouse, to characterize the spatiotemporal evolution of the lesion and to quantify the changes in lesion volume and length with time. The MR intensity patterns on Day 1 showed acute injuries as focal in one group of three mice and as diffuse in the remaining group of four mice. The focal injuries appeared as a region of hypointensity with well-defined boundaries. These injuries first enlarged on Day 7, but then shrunk slightly by Days 14 and 28. In contrast, the diffuse injuries were initially obscure on Day 1, mainly because of loss of contrast between gray and white matters. On Day 7, lesions expanded asymptotically in both rostral and caudal directions with respect to the epicenter, and maintained its size on Days 14 and 28. Previous studies based on postmortem histological analysis have reported lesions behaving more like in the focal group. However, this new injury with diffuse characteristics may have important implications for SCI research carried out with mice. Unique experiments on genetically engineered mice with altered neuroinflammatory response should help clarify the origin of these differences in the lesion formation.

A series of models of non-thermal high voltage electrical injuries

Although many models of electrical injury have been established, none of them are completely typical of the clinical features of electrical injury. As a result, research based on these models were incapable of explaining many clinical phenomena such as continuous tissue necrosis and also were unable to cope with high ratio of amputation of extremities. In order to investigate the mechanism of electrical injuries and better model the condition with similar clinical characteristics we developed a new model. Seventy -five New Zealand rabbits were employed in this study, of them 45 were used in a preliminary experiment including the selection of the size of electrode plate area, damaged extent, time length of electrical injury and interval length between two injuries and so on. Another 30 rabbits were equally divided into five groups with electrical injury times of 6, 12, 18, 24 and 30 cycles, respectively. Observations were made using clinical anatomical exploration, with quantification using an IDBI scale on the 2nd, 8th, 24th, 48th hours and 5th, 15th days, and TC-99m-DMP isotope scanning and γ photography at 2nd hour and 5th day in post-injury, respectively. The results showed the effective electric field strength was 17,000 V/m, mean current intensity was 554 mA, average current density was 137 mA/cm 2 beneath the small electrode plate with 21 mA/ cm 2 beneath big one, and average increase of tissue temperature was 1.73 °C during injury process which excluded the possibility of thermal injury. One single wound injury beneath the small plate of the experimental rabbits with loss of injured extremities from 5th to 15th post-injury days in groups 3–5 and obviously progressive tissue necrosis in and outside the wounds were obtained. A series of electrical injured models from mild, moderate, severe, extra severe, and destructive which was exactly similar to the clinical features of electrical injury cases was established.

Traumatic Brain Injury Produces Delay-Dependent Memory Impairment in Rats

Memory impairment following traumatic brain injury (TBI) is common in both humans and animals. A noteworthy feature of memory dysfunction in human TBI is impaired memory performance that is dependent on the delay between initial learning and recall of information. However, previous studies of TBI-induced memory impairment in animals have failed to control for the initial amount of learning between sham and injured animals. The present study demonstrates that experimental TBI in rats produces delay-dependent memory impairment, even when the initial degree of learning is controlled for. Animals were injured at a moderate level of lateral fluid percussion (LFP) injury (n = 10) or received a sham injury (n = 9), and then trained in a water T-maze version of the delayed-non-matching-to-place (DNMP) task beginning 10 days post-injury. Acquisition training consisted of 15 trials per day on post-injury days 11-15 using a minimal (7-sec) delay between the sample and choice phases of the task. Following acquisition, the delay between the sample and choice phases of the task was progressively increased to 15, 30, and 120 sec. Injured animals acquired the task at the same rate as sham animals and performed equally well at the 15-sec delay (p > 0.05). However, as the delay increased to 30 and 120 sec, the performance of the injured animals deteriorated (p < 0.05). These results indicate that LFP injury produces delay-dependent memory impairments in rats. This is therefore a valid model of an important feature of memory impairment in human TBI, and should be a useful addition to the available methods for assessing memory impairment and the effect of therapeutic interventions after TBI.

Delayed, Post-Injury Treatment with Aniracetam Improves Cognitive Performance after Traumatic Brain Injury in Rats

Chronic cognitive impairment is an enduring aspect of traumatic brain injury (TBI) in both humans and animals. Treating cognitive impairment in the post-traumatic stages of injury often involves the delivery of pharmacologic agents aimed at specific neurotransmitter systems. The current investigation examined the effects of the nootropoic drug aniracetam on cognitive recovery following TBI in rats. Three experiments were performed to determine (1) the optimal dose of aniracetam for treating cognitive impairment, (2) the effect of delaying drug treatment for a period of days following TBI, and (3) the effect of terminating drug treatment before cognitive assessment. In experiment 1, rats were administered moderate fluid percussion injury and treated with vehicle, 25, or 50 mg/kg aniracetam for 15 days. Both doses of aniracetam effectively reduced injury-induced deficits in the Morris water maze (MWM) as measured on postinjury days 11-15. In experiment 2, injured rats were treated with 50 mg/kg aniracetam or vehicle beginning on day 11 postinjury and continuing for 15 days. MWM performance, assessed on days 26-30, indicates that aniracetam-treated animals performed as well as sham-injured controls. In experiment 3, animals were injured and treated with aniracetam for 15 days. Drug treatment was terminated during MWM testing on postinjury days 16-20. In this experiment, aniracetam-treated rats did not perform better than vehicle-treated rats. The results of these experiments indicate that aniracetam is an effective treatment for cognitive impairment induced by TBI, even when treatment is delayed for a period of days following injury.