Effects of low intensity vibration on bone and muscle in rats with spinal cord injury.

UNLABELLED: Spinal cord injury (SCI) causes rapid and marked bone loss. The present study demonstrates that low-intensity vibration (LIV) improves selected biomarkers of bone turnover and gene expression and reduces osteoclastogenesis, suggesting that LIV may be expected to benefit to bone mass, resorption, and formation after SCI. INTRODUCTION: Sublesional bone is rapidly and extensively lost following spinal cord injury (SCI). Low-intensity vibration (LIV) has been suggested to reduce loss of bone in children with disabilities and osteoporotic women, but its efficacy in SCI-related bone loss has not been tested. The purpose of this study was to characterize effects of LIV on bone and bone cells in an animal model of SCI. METHODS: The effects of LIV initiated 28 days after SCI and provided for 15 min twice daily 5 days each week for 35 days were examined in female rats with moderate severity contusion injury of the mid-thoracic spinal cord. RESULTS: Bone mineral density (BMD) of the distal femur and proximal tibia declined by 5 % and was not altered by LIV. Serum osteocalcin was reduced after SCI by 20 % and was increased by LIV to a level similar to that of control animals. The osteoclastogenic potential of bone marrow precursors was increased after SCI by twofold and associated with 30 % elevation in serum CTX. LIV reduced the osteoclastogenic potential of marrow precursors by 70 % but did not alter serum CTX. LIV completely reversed the twofold elevation in messenger RNA (mRNA) levels for SOST and the 40 % reduction in Runx2 mRNA in bone marrow stromal cells resulting from SCI. CONCLUSION: The findings demonstrate an ability of LIV to improve selected biomarkers of bone turnover and gene expression and to reduce osteoclastogenesis. The study indicates a possibility that LIV initiated earlier after SCI and/or continued for a longer duration would increase bone mass.

Postinjury treatment with rolipram increases hemorrhage after traumatic brain injury.

The pathology caused by traumatic brain injury (TBI) is exacerbated by the inflammatory response of the injured brain. Two proinflammatory cytokines that contribute to inflammation after TBI are tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). From previous studies using the parasagittal fluid-percussion brain injury model, we reported that the anti-inflammatory drug rolipram, a phosphodiesterase 4 inhibitor, reduced TNF-α and IL-1ß levels and improved histopathological outcome when administered 30 min prior to injury. We now report that treatment with (±)-rolipram given 30 min after injury significantly reduced TNF-α levels in the cortex and hippocampus. However, postinjury administration of (±)-rolipram significantly increased cortical contusion volume and increased atrophy of the cortex compared with vehicle-treated animals at 10 days postinjury. Thus, despite the reduction in proinflammatory cytokine levels, histopathological outcome was worsened with post-TBI (±)-rolipram treatment. Further histological analysis of (±)-rolipram-treated TBI animals revealed significant hemorrhage in the contused brain. Given the well-known role of (±)-rolipram of increasing vasodilation, it is likely that (±)-rolipram worsened outcome after fluid-percussion brain injury by causing increased bleeding.

Age-related differences in the local cellular and molecular responses to injury in developing spinal cord of the opossum, Monodelphis domestica.

Immature spinal cord, unlike adult, has an ability to repair itself following injury. Evidence for regeneration, structural repair and development of substantially normal locomotor behaviour comes from studies of marsupials due to their immaturity at birth. We have compared morphological, cellular and molecular changes in spinal cords transected at postnatal day (P)7 or P14, from 3 h to 2 weeks post-injury, in South American opossums (Monodelphis domestica). A bridge between severed ends of cords was apparent 5 days post-injury in P7 cords, compared to 2 weeks in P14. The volume of neurofilament (axonal) material in the bridge 2 weeks after injury was 30% of control in P7- but < 10% in P14-injured cords. Granulocytes accumulated at the site of injury earlier (3 h) in P7 than in P14 (24 h)-injured animals. Monocytes accumulated 24 h post-injury and accumulation was greater in P14 cords. Accumulation of GFAP-positive astrocytes at the lesion occurred earlier in P14-injured cords. Neurites and growth cones were identified ultrastructurally in contact with astrocytes forming the bridge. Results using mouse inflammatory gene arrays showed differences in levels of expression of many TGF, TNF, cytokine, chemokine and interleukin gene families. Most of the genes identified were up-regulated to a greater extent following injury at P7. Some changes were validated and quantified by RT-PCR. Overall, the results suggest that at least some of the greater ability to recover from spinal cord transection at P7 compared to P14 in opossums is due to differences in inflammatory cellular and molecular responses.

Histopathological and behavioral characterization of a novel cervical spinal cord displacement contusion injury in the rat.

Cervical contusive trauma accounts for the majority, of human spinal cord injury (SCI), yet experimental use of cervical contusion injury models has been limited. Considering that (1) the different ways of injuring the spinal cord (compression, contusion, and transection) induce very different processes of tissue damage and (2) the architecture of the spinal cord is not uniform, it is important to use a model that is more clinically applicable to human SCI. Therefore, in the current study we have developed a rat model of contusive, cervical SCI using the Electromagnetic Spinal Cord Injury Device (ESCID) developed at Ohio State University (OSU) to induce injury by spinal cord displacement. We used the device to perform mild, moderate and severe injuries (0.80, 0.95, and 1.1 mm displacements, respectively) with a single, brief displacement of <20 msec upon the exposed dorsal surface of the C5 cervical spinal cord of female (180-200 g) Fischer rats. Characterization of the model involved the analysis of the temporal histopathological progression of the injury over 9 weeks using histochemical stains to analyze white and gray mater integrity and immunohistochemistry to examine cellular changes and physiological responses within the injured spinal cord. Accompanying the histological analysis was a comprehensive determination of the behavioral functionality of the animals using a battery of motor tests. Characterization of this novel model is presented to enable and encourage its future use in the design and experimental testing of therapeutic strategies that may be used for human SCI.

The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma.

Traumatic injury to the brain and spinal cord results in an early inflammatory response that is initiated by the release of proinflammatory cytokines followed by the infiltration and accumulation of polymorphonuclear leukocytes (PMNLs). The role of the inflammatory cascade on traumatic outcome remains controversial. Pleiotropic cytokines appear to function both protectively and destructively. The induction of cytokines can lead to the expression of the inducible form of nitric oxide synthase (iNOS), which in turn provokes the release of excessive amounts of nitric oxide (NO) that may participate in the pathogenesis of tissue injury. Hypothermia has been reported by various groups to be neuroprotective in brain and spinal cord trauma. We studied the effect of therapeutic hypothermia on cerebral IL-1beta concentrations, PMNL accumulation and iNOS activity after traumatic brain injury (TBI) and spinal cord injury (SCI). Based on current data therapeutic hypothermia may protect in models of traumatic injury by modulating deleterious inflammatory processes.

Comparison of iNOS inhibition by antisense and pharmacological inhibitors after spinal cord injury.

Inducible nitric oxide synthase (iNOS) is a key mediator of inflammation during pathological conditions. We examined, through the use of selective iNOS inhibitors, the role of iNOS in specific pathophysiological processes after spinal cord injury (SCI), including astrogliosis, blood-spinal cord barrier (BSCB) permeability, polymorphonuclear leukocyte infiltration, and neuronal cell death. Administration of iNOS antisense oligonucleotides (ASOs) (intraspinally at 3 h) or the pharmacological inhibitors, N-[3(Aminomethyl) benzyl] acetamidine (1400 W) (i.v./i.p. 3 and 9 h) or aminoguanidine (i.p. at 3 and 9 h) after moderate contusive injury decreased the number of iNOS immunoreactive cells at the injury site by 65.6% (iNOS ASOs), 62.1% (1400 W), or 59% (aminoguanidine) 24 h postinjury. iNOS activity was reduced 81.8% (iNOS ASOs), 56.7% (1400 W), or 67.9% (aminoguanidine) at this time. All iNOS inhibitors reduced the degree of BSCB disruption (plasma leakage of rat immunoglobulins), with iNOS ASO inhibition being more effective (reduced by 58%). Neutrophil accumulation within the injury site was significantly reduced by iNOS ASOs and 1400 W by 78.8% and 20.9%, respectively. Increased astrogliosis was diminished with iNOS ASOs but enhanced following aminoguanidine. Detection of necrotic and apoptotic neuronal cell death by propidium iodide and an FITC-conjugated Annexin V antibody showed that iNOS inhibition could significantly retard neuronal cell death rostral and caudal to the injury site. These novel findings indicate that acute inhibition of iNOS is beneficial in reducing several pathophysiological processes after SCI. Furthermore, we demonstrate that the antisense inhibition of iNOS is more efficacious than currently available pharmacological agents.

Regulation of caspases and XIAP in the brain after asphyxial cardiac arrest in rats.

The aim of this study was to determine whether hypoxic-ischemia from asphyxial cardiac arrest activates brain caspases-1 and -3, and the anti-apoptotic protein, XIAP. Asphyxial cardiac arrest in rats was used to induce hypoxic-ischemia. A pan-caspase inhibitor (zVAD) was given in the treatment group. At 72 h after reperfusion, caspase-3 and XIAP expression were present in multiple vulnerable brain regions, whereas caspase-1 was predominantly found in the CA1 hippocampus. zVAD significantly reduced expression of caspases and XIAP and the number of ischemic neurons in the CA1 hippocampus while neurological deficit scores were improved. We conclude that hypoxic-ischemia increases caspases-1 and-3, and XIAP expression. Treatment with zVAD significantly decreases caspase and XIAP expression in these brain regions and improves neurological outcome.

Posttraumatic hypothermia is neuroprotective in a model of traumatic brain injury complicated by a secondary hypoxic insult.

OBJECTIVE: Human traumatic brain injury frequently results in secondary complications, including hypoxia. In previous studies, we have reported that posttraumatic hypothermia is neuroprotective and that secondary hypoxia exacerbates histopathologic outcome after fluid-percussion brain injury. The purpose of this study was to assess the therapeutic effects of mild (33 degrees C) hypothermia after fluid-percussion injury combined with secondary hypoxia. In addition, the importance of the rewarming period on histopathologic outcome was investigated. DESIGN: Prospective experimental study in rats. SETTING: Experimental laboratory in a university teaching hospital. INTERVENTION: Intubated, anesthetized rats underwent normothermic parasagittal fluid-percussion brain injury (1.8-2.1 atmospheres) followed by either 30 mins of normoxia (n = 6) or hypoxic (n = 6) gas levels and by 4 hrs of normothermia (37 degrees C). In hypothermic rats, brain temperature was reduced immediately after the 30-min hypoxic insult and maintained for 4 hrs. After hypothermia, brain temperature was either rapidly (n = 6) or slowly (n = 5) increased to normothermic levels. Rats were killed 3 days after traumatic brain injury, and contusion volumes were quantitatively assessed. MEASUREMENTS AND MAIN RESULTS: As previously shown, posttraumatic hypoxia significantly increased contusion volume compared with traumatic brain injury-normoxic animals (p <.02). Importantly, although posttraumatic hypothermia followed by rapid rewarming (15 mins) failed to decrease contusion volume, those animals undergoing a slow rewarming period (120 mins) demonstrated significantly (p <.03) reduced contusion volumes, compared with hypoxic normothermic rats. CONCLUSIONS: These data emphasize the beneficial effects of posttraumatic hypothermia in a traumatic brain injury model complicated by secondary hypoxia and stress the importance of the rewarming period in this therapeutic intervention.

Apoptotic and antiapoptotic mechanisms after traumatic brain injury.

Caspase and inhibitor of apoptosis (IAP) expression was examined in rats subjected to moderate traumatic brain injury (TBI) using a parasagittal fluid-percussion brain insult (1.7 to 2.2 atm). Within 1 hour after injury, caspase-8 and -9, two initiators of apoptosis, were predominantly expressed in superficial cortical areas adjacent to the impact site and in the thalamus. Caspase-3, an effector caspase, was evident at 6 hours throughout the traumatized cerebral cortex and hippocampus. Moreover, the authors observed that XIAP, cIAP-1, and cIAP-2, members of the IAP family, were constitutively expressed in the brain. Colocalization of XIAP-immunolabled cells with cell-specific markers indicated that XIAP is expressed within neurons and a subpopulation of oligodendrocytes. Immunoblots of brain extracts revealed that the processed forms of caspase-8, -9, and -3 are present as early as 1 hour after trauma. The appearance of activated caspases corresponded with the detection of cleavage of XIAP into fragments after injury and a concomitant increase in the levels of cIAP-1 and cIAP-2 in the traumatized hemispheres. The current data are consistent with the hypotheses that caspases in both the extrinsic and intrinsic apoptotic pathways are activated after moderate TBI and that IAPs may have a protective role within the brain with alterations in levels and cleavage of IAPs that contribute to cell death in this setting.

Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females.

An important consideration in traumatic brain injury (TBI) in females is the influence of hormones on recovery. Recent studies in both cerebral ischemia and TBI have demonstrated an attenuation in both damage and neurologic recovery following hormonal treatment. However, the ability of endogenous hormone levels to provide neuropathological protection after fluid percussion (FP) brain injury has not been studied. The purpose of this experiment was to determine whether endogenous circulating hormones in the female rat could provide neuroprotection compared to males and ovariectomized female animals. Sixty-four Sprague-Dawley rats underwent a moderate (1.7-2.2 atm) right parasagittal FP injury. Intact females (i.e., nonovariectomized) were subjected to injury either during the proestrous (TBI-FP, n = 18) phase of their cycle or nonproestrous (TBI-FNP, n = 19) phase. A separate group of females were ovariectomized (TBI-OVX, n = 10) 10 days prior to FP injury in order to reduce hormone levels. Male animals were also traumatized (TBI-M, n = 17). Appropriate sham controls (Sham-FP, n = 2; Sham-FNP, n = 2; Sham-OVX, n = 2; Sham-M, n = 2) also underwent all aspects of surgery except for the actual FP injury. All groups were sacrificed 3 days following TBI for analysis. Both intact female groups had significantly (p < 0.05) smaller cortical contusions compared to male animals. In addition to this finding, the TBI-FNP group was significantly (p < 0.04) different from the ovariectomized female animals. Ovariectomized rats had larger areas of damage compared to intact females. The TBI-OVX group's cortical contusion volume was similar to male animals. These results provide evidence for endogenous hormonal histopathological protection following parasagittal FP brain injury. The use of hormone therapy after TBI warrants continued exploration.

Behavioral, electrophysiological, and histopathological consequences of mild fluid-percussion injury in the rat.

Metabolic dysfunction in the relay nuclei of the rat vibrissa circuit follows traumatic brain injury (TBI). This study examined the effects of mild (1.4-1.5 atm) parasagittal fluid-percussion injury on the electrophysiology of this circuit. TBI caused significant reductions in slope and increases in latency of vibrissa-evoked field potentials 3 days after injury. Assessment of open-field swimming revealed an increase in thigmotaxis 2 days after injury. TBI caused mild selective cortical damage and limited axonal swelling at the injury site. Thus mild injury disrupts somatosensory electrophysiology and exploratory behavior.

Influence of posttraumatic hypoxia on behavioral recovery and histopathological outcome following moderate spinal cord injury in rats.

Pulmonary dysfunction leading to secondary hypoxia is a common complication of spinal cord injury (SCI). The purpose of this study was to clarify the behavioral and histopathological consequences of posttraumatic hypoxia in an established model of traumatic SCI. Forty-five female Sprague-Dawley rats were randomly assigned to one of four groups, including (1) laminectomy and normoxia (n = 10), (2) laminectomy and hypoxia (n = 11), (3) NYU weight-drop and normoxia (n = 12), and (4) NYU weight-drop and hypoxia (n = 11). For these studies, a moderate injury was induced by adjusting the height of the weight drop (10 g) to 12.5 mm above the exposed spinal cord (T10). Immediately after injury, PaO2 in the hypoxic rats was kept between 30 and 35 mm Hg for 30 min. PaO2 in the normoxic group was maintained over 100 mm Hg, while PaCO2 in all rats was maintained at 35-40 mm Hg. The behavior of the rats was checked every 7 days using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. Rats were sacrificed at 8 weeks for quantitative histopathological analysis of lesion areas. During the hypoxic insults, the mean arterial blood pressure dropped in both sham control and weight-drop rats (p < 0.01). At the end of the 8-week monitoring period, BBB scores were 12.5 +/- 3.1 (mean +/- SEM) and 14.2 +/- 3.4 in the normoxic and hypoxic traumatized rats, respectively. No significant difference between the traumatized groups was documented with BBB monitoring. In contrast, the percent of gray matter necrosis at the impact epicenter was significantly increased in hypoxic versus normoxic SCI rats (p < 0.01). These data demonstrate that posttraumatic hypoxia complicated by mild hypotension aggravates the histopathological consequences of SCI and further emphasize the need to control for secondary hypoxic insults after experimental and clinical SCI. Potential explanations for the lack of a correlation between the behavioral and histopathological findings are discussed.

Delayed hemorrhagic hypotension exacerbates the hemodynamic and histopathologic consequences of traumatic brain injury in rats.

Alterations in cerebral autoregulation and cerebrovascular reactivity after traumatic brain injury (TBI) may increase the susceptibility of the brain to secondary insults, including arterial hypotension. The purpose of this study was to evaluate the consequences of mild hemorrhagic hypotension on hemodynamic and histopathologic outcome after TBI. Intubated, anesthetized male rats were subjected to moderate (1.94 to 2.18 atm) parasagittal fluid-percussion (FP) brain injury. After TBI, animals were exposed to either normotension (group 1: TBI alone, n = 6) or hypotension (group 2: TBI + hypotension, n = 6). Moderate hypotension (60 mm Hg/30 min) was induced 5 minutes after TBI or sham procedures by hemorrhage. Sham-operated controls (group 3, n = 7) underwent an induced hypotensive period, whereas normotensive controls (group 4, n = 4) did not. For measuring regional cerebral blood flow (rCBF), radiolabeled microspheres were injected before, 20 minutes after, and 60 minutes after TBI (n = 23). For quantitative histopathologic evaluation, separate groups of animals were perfusion-fixed 3 days after TBI (n = 22). At 20 minutes after TBI, rCBF was bilaterally reduced by 57% +/- 6% and 48% +/- 11% in cortical and subcortical brain regions, respectively, under normotensive conditions. Compared with normotensive TBI rats, hemodynamic depression was significantly greater with induced hypotension in the histopathologically vulnerable (P1) posterior parietal cortex (P < 0.01). Secondary hypotension also increased contusion area at specific bregma levels compared with normotensive TBI rats (P < 0.05), as well as overall contusion volume (0.96 +/- 0.46 mm(3) vs. 2.02 +/- 0.51 mm(3), mean +/- SD, P < 0.05). These findings demonstrate that mild hemorrhagic hypotension after FP injury worsens local histopathologic outcome, possibly through vascular mechanisms.

Detrimental effects of systemic hyperthermia on locomotor function and histopathological outcome after traumatic spinal cord injury in the rat.

OBJECTIVE: Posttraumatic hyperthermia has been demonstrated to worsen neurological outcome in models of brain injury. The purpose of this study was to examine the effects of systemic hyperthermia on locomotor and morphological outcome measures after traumatic spinal cord injury (SCI) in the rat. METHODS: After a T10 laminectomy, spinal cord contusions were produced from a height of 12.5 mm onto exposed cords (NYU Impactor; New York University Neurosurgery Laboratory, New York, NY) in adult rats that were divided into three groups. Group 1 (n = 9) underwent whole body hyperthermia (rectal temperature, 39.5 degrees C) 30 minutes postinjury for 4 hours, Group 2 (n = 8) underwent normothermia (rectal temperature, 37 degrees C) 30 minutes postinjury for 4 hours, and Group 3 (n = 10) underwent traumatic SCI with no postinjury thermal treatment. Twice-weekly assessments of locomotor function were made during a 6-week survival period using the Basso-Beattie-Breshnahan locomotor rating scale. Forty-four days after injury, animals were perfused, and their spinal cords serially sectioned. Sections were stained with hematoxylin, eosin, and Luxol fast blue for histopathological analysis. The percentage of tissue damage was quantitatively determined by using computer-aided image analysis. RESULTS: The results showed that 4 hours of postinjury hyperthermia significantly worsened locomotor outcome (final Basso-Beattie-Breshnahan scores were 9.7 +/- 0.3 [Group 1] versus 10.8 +/- 0.4 [Group 2] versus 11.3 +/- 0.3 [Group 3]) and led to an increase in the percentage of tissue damage (32.9 + 3.2% [Group 1] versus 22.3 +/- 2.8% [Group 3]). CONCLUSION: These data suggest that complications of SCI (e.g., fever, infection) leading to an elevation of systemic temperature may add to the severity of secondary injury associated with traumatic SCI and significantly affect neurological outcome.

Apoptotic and anti-apoptotic mechanisms following spinal cord injury.

A number of studies have provided evidence that cell death from moderate traumatic spinal cord injury (SCI) is regulated, in part, by apoptosis that involves the caspase family of cysteine proteases. However, little or no information is available about anti-apoptotic mechanisms mediated by the inhibitors of apoptosis (IAP) family of proteins that inhibit cell death pathways. In the present study, we examined caspase and IAP expression in spinal cords of rats subjected to moderate traumatic injury. Within 6 h after injury, caspase-8 and-9 (2 initiators of apoptosis) were predominantly present in gray matter neurons within the lesion epicenter. By 3 days following spinal cord injury (SCI), caspase-8 and-9 immunoreactivity was localized to gray and white matter cells, and by 7 days following SCI, both upstream caspases were expressed in cells within white matter or within foamy macrophages in gray matter. Caspase-3, an effector caspase, was evident in a few fragmented cells in gray matter at 24 h following injury and then localized to white matter in later stages. Thus, distinct patterns of caspase expression can be found in the spinal cord following injury. XIAP, cIAP-1, and cIAP-2, members of the IAP family, were constitutively expressed in the cord. Immunoblots of spinal cord extracts revealed that the processed forms of caspases-8 and-9 and cleavage of PARP are present as early as 6 h following trauma. The expression of caspases corresponded with the detection of cleavage of XIAP into 2 fragments following injury. cIAP-1 and cIAP-2 expression remained constant during early periods following SCI but demonstrated alterations by 7 days following SCI. Our data are consistent with the idea that XIAP may have a protective role within the spinal cord, and that alteration in cleavage of XIAP may regulate cell death following SCI.

Role of nitric oxide in the cerebrovascular and thermoregulatory response to interleukin-1 beta.

Central administration of interleukin-1 beta (IL-1 beta) increases cerebral blood flow (CBF) and body temperature, in part, through the production of prostaglandins. In previous studies, the temporal relationship between these effects of IL-1 beta have not been measured. In this study, we hypothesized that the increase in CBF occurs before any change in brain or body temperature and that the cerebrovascular and thermoregulatory effects of IL-1 beta would be attenuated by inhibiting the production of nitric oxide (NO). Adult male rats received 100 ng intracerebroventricular (icv) injection of IL-1 beta, and cortical CBF (cCBF) was measured by laser-Doppler in the contralateral cerebral cortex. A central injection of IL-1 beta caused a rapid increase in cCBF to 133 +/- 12% of baseline within 15 min and to an average of 137 +/- 12% for the remainder of the 3-h experiment. Brain and rectal temperature increased by 0.4 +/- 0.2 and 0.5 +/- 0.2 degrees C, but not until 45 min after IL-1 beta administration. Pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg iv) completely prevented the changes in cCBF and brain and rectal temperature induced by IL-1 beta. L-Arginine (150 mg/kg iv) partially reversed the effects of L-NAME and resulted in increases in both cCBF and temperature. These findings suggest that the vasodilatory effects of IL-1 beta in the cerebral vasculature are independent of temperature and that NO plays a major role in both the cerebrovascular and thermoregulatory effects of centrally administered IL-1 beta.

Therapeutic effects of environmental enrichment on cognitive function and tissue integrity following severe traumatic brain injury in rats.

Postinjury environmental enrichment (EE) has been shown to alter functional and anatomical outcomes in a number of injury paradigms, including traumatic brain injury (TBI). The question of whether EE alters functional outcome following TBI in a model which produces overt histopathological consequences has not been addressed. We investigated this question using the severe, parasagittal fluid percussion injury (FPI) model. Rats (n = 7 per group, enriched and standard for behavior; n = 15 per group for histology) underwent severe (2.2-2.6 atm) FPI, with sham-operated rats (n = 7 per group, enriched and standard for behavior; n = 6 enriched, n = 3 standard for histology) serving as controls. Animals were allowed to recover for 11 days either in standard single housing or together (injured and sham) in an enriched environment consisting of a 92 x 61 x 77-cm ferret cage filled with various stimulatory objects. Consistent with earlier reports, injured animals recovering in the enriched environment showed significantly (P < 0.05) shorter latencies to find the platform in a Morris Water Maze task versus injured/standard animals on day 12 post-TBI. However, both injured groups showed significant deficits versus sham groups (P < 0.05). There were no differences between the sham/enriched and sham/standard groups. No significant group differences in swim speed were observed. At 14 days post-TBI, enriched animals had approximately twofold smaller lesion areas in regions of the cerebral cortex posterior to the injury epicenter (-4.5, -5.8, -6.8 mm relative to bregma; P < 0.05) compared to injured/standard animals. In addition, overall lesion volume for the entire injured cortical hemisphere was significantly smaller in animals recovering in the enriched environment. These results indicate that noninvasive environmental stimulation is beneficial in attenuating cognitive deficits and preserving tissue integrity in a TBI model which causes cerebral contusion and cell death.

Chronic metabolic sequelae of traumatic brain injury: prolonged suppression of somatosensory activation.

Injuries to the brain acutely disrupt normal metabolic function and may deactivate functional circuits. It is unknown whether these metabolic abnormalities improve over time. We used 2-deoxyglucose (2-DG) autoradiographic image-averaging to assess local cerebral glucose utilization (lCMR(Glc)) of the rat brain 2 mo after moderate (1.7-2.1 atm) fluid-percussion traumatic brain injury (FPI). Four animal groups (n = 5 each) were studied: sham-injured rats with and without stimulation of the vibrissae-barrel field ipsilateral to injury; and animals with prior FPI, with or without this stimulation. In sham-injured rats, resting lCMR(Glc) was normal, and vibrissae stimulation produced right-sided metabolic activation of the ventrolateral thalamic and somatosensory-cortical projection areas. In rats with prior injury, lCMR(Glc) contralateral to injury was normal, but lCMR(Glc) of the ipsilateral forebrain was depressed by approximately 38-45% compared with shams. Whisker stimulation in rats with prior trauma failed to induce metabolic activation of either cortex or thalamus. Image-mapping of histological material obtained in the same injury model was undertaken to assess the possible influence of injury-induced regional brain atrophy on computed lCMR(Glc); an effect was found only in the lateral cortex at the trauma epicenter. Our results show that, 2 mo after trauma, resting cerebral metabolic perturbations persist, and the whisker-barrel somatosensory circuit shows no signs of functional recovery.

Beneficial effects of modest systemic hypothermia on locomotor function and histopathological damage following contusion-induced spinal cord injury in rats.

OBJECT: Local spinal cord cooling (LSCC) is associated with beneficial effects when applied following ischemic or traumatic spinal cord injury (SCI). However, the clinical application of LSCC is associated with many technical difficulties such as the requirement of special cooling devices, emergency surgery, and complicated postoperative management. If hypothermia is to be considered for future application in the treatment of SCI, alternative approaches must be developed. The objectives of the present study were to evaluate 1) the relationship between systemic and epidural temperature after SCI; 2) the effects of modest systemic hypothermia on histopathological damage at 7 and 44 days post-SCI; and 3) the effects of modest systemic hypothermia on locomotor outcome at 44 days post-SCI. METHODS: A spinal cord contusion (12.5 mm at T-10) was produced in adult rats that had been randomly divided into two groups. Group 1 rats (seven in Experiment 1; 12 in Experiment 2) received hypothermic treatment (epidural temperature 32-33 degrees C) 30 minutes postinjury for 4 hours; Group 2 rats (nine in Experiment 1; eight in Experiment 2) received normothermic treatment (epidural temperature 37 degrees C) 30 minutes postinjury for 4 hours. Blood pressure, blood gas levels, and temperatures (epidural and rectal) were monitored throughout the 4-hour treatment period. Twice weekly assessment of locomotor function was performed over a 6-week survival period by using the Basso-Beattie-Bresnahan locomotor rating scale. Seven (Experiment 1) and 44 (Experiment 2) days after injury, animals were killed, perfused, and their spinal cords were serially sectioned. The area of tissue damage was quantitatively analyzed from 16 longitudinal sections selected from the central core of the spinal cord. CONCLUSIONS: The results showed that 1) modest changes in the epidural temperature of the spinal cord can be produced using systemic hypothermia; 2) modest systemic hypothermia (32-33 degrees C) significantly protects against locomotor deficits following traumatic SCI; and 3) modest systemic hypothermia (32-33 degrees C) reduces the area of tissue damage at both 7 and 44 days postinjury. Although additional research is needed to study the therapeutic window and long-term benefits of systemic hypothermia, these data support the possible use of modest systemic hypothermia in the treatment of acute SCI.