Combined Traumatic Brain Injury Research Articles

Elevation of hippocampal MMP-3 expression and activity during trauma-induced synaptogenesis

The matrix metalloproteinase (MMP) enzyme family contributes to the regulation of a variety of brain extracellular matrix molecules. In order to assess their role in synaptic plasticity following traumatic brain injury (TBI), we compared expression of stromelysin-1 (MMP-3) protein and mRNA in two rodent models of TBI exhibiting different levels of recovery: adaptive synaptic plasticity following central fluid percussion injury and maladaptive synaptic plasticity generated by combined TBI and bilateral entorhinal cortical lesion (TBI + BEC). We sampled the hippocampus at 7 days postinjury, targeting a selectively vulnerable brain region and a survival interval exhibiting rapid synaptogenesis. We report elevated expression of hippocampal MMP-3 mRNA and protein after TBI. MMP-3 immunohistochemical staining showed increased protein levels relative to sham-injured controls, primarily localized to cell bodies within the deafferented dendritic laminae. Injury-related differences in MMP-3 protein were also observed. TBI alone elevated MMP-3 immunobinding over the stratum lacunosum moleculare (SLM), inner molecular layer and hilus, while TBI + BEC generated more robust increases in MMP-3 reactivity within the deafferented SLM and dentate molecular layer (DML). Double labeling with GFAP confirmed the presence of MMP-3 within reactive astrocytes induced by each injury model. Semi-quantitative RT-PCR revealed that MMP-3 mRNA also increased after each injury, however, the combined insult induced a much greater elevation than fluid percussion alone: 1.9-fold vs. 79%, respectively. In the TBI + BEC model, MMP-3 up-regulation was spatio-temporally correlated with increased enzyme activity, an effect which was attenuated with the neuroprotective compound MK-801. These results show that distinct pathological conditions elicited by TBI can differentially affect MMP-3 expression during reactive synaptic plasticity. Notably, these effects are both transcriptional and translational and are correlated with functionally active enzyme.

Serum IL-6, IL-8 and IL-10 Levels in Multiple Trauma Compared to Traumatic Brain Injury and Combined Trauma

Background: In recent studies, the role of cytokines in traumatic brain injury (TBI) has been identified and the intrathecal origin of cytokines demonstrated. The question, however, whether or not there is any difference in serum cytokines between TBI, multiple trauma (MT) and the combination of both (MT with TBI) which may significantly contribute to the final outcome, has not been fully examined yet. Patients and Methods: In a prospective study three different groups of trauma patients were monitored for serum cytokine levels over a 7-day period, multiple organ dysfunction (MOD) and final outcome. The patients eligible for this study must have sustained either an isolated traumatic brain injury (TBI), or multiple trauma (MT) without TBI, or a multiple trauma in combination with TBI (MT+TBI). Results: In patients with isolated TBI (n=40, cranial Abbreviated Injury Score [AIShead]=4.4±0.8, total Injury Severity Score [ISS]=17.1±5.1), serum interleukin-(IL-)6 levels ranged between 150 and 200 pg/ml within the first 48 h followed by a constant decline (<100 pg/ml) over the 7-day study period. By contrast, serum IL-6 levels of multiply injured patients (n=10, AIShead=1.0±1.2, total ISS=29.9±5.2) were significantly (p<0.05) increased (range 350–400 pg/ml) after trauma, also followed by a constant decline. In patients suffering from MT including TBI (n=44, AIShead=4.1±0.9, total ISS=31.8±5.8), serum IL-6 levels were also significantly (p<0.05) higher after trauma compared to TBI patients, but not significantly different from MT patients without TBI. IL-8 and IL-10 serum levels demonstrated a similar pattern, with low cytokine serum levels in the TBI group but significantly high serum levels in both MT groups. The multiple organ dysfunction (MOD) score of Marshall et al revealed no significant change in the TBI group over the 7-day period. In MT patients the MOD score deteriorated transiently around day 3, whereas in the combined trauma group the MOD score was elevated over the entire study period compared to both other trauma groups. Mortality was 27.5% in TBI patients, 0 in MT, and 52.3% in combined trauma. Conclusion: TBI alone does not result in a significant systemic inflammatory response, whereas the combination of TBI and MT seems to enhance the inflammatory reaction ending in a higher MOD incidence and MOD-related mortality as compared to MT without TBI.

Traumatic brain injury-induced changes in gene expression and functional activity of mitochondrial cytochrome C oxidase.

Traumatic brain injury (TBI) is documented to have detrimental effects on CNS metabolism, including alterations in glucose utilization and the depression of mitochondrial oxidative phosphorylation. Studies on mitochondrial metabolism have also provided evidence for reduced activity of the cytochrome oxidase complex of the electron transport chain (complex IV) after TBI and an immediate (lhr) reduction in mitochondrial state 3 respiratory rate, which can persist for up to 14 days postinjury. Using differential display methods to screen for differences in gene expression, we have found that cytochrome c oxidase II (COII), a mitochondrial encoded subunit of complex IV, is upregulated following TBI. Since COII carries a binding site for cytochrome c in the respiratory chain, and since it is required for the passage of chain electrons to molecular oxygen, driving the production of ATP, we hypothesized that metabolic dysfunction resulting from TBI alters COII gene expression directly, perhaps influencing the synaptic plasticity that occurs during postinjury recovery processes. To test this hypothesis, we documented COII mRNA expression and complex IV (cytochrome c oxidase) functional activity at 7 days postinjury, focusing on the long-term postinjury period most closely associated with synaptic reorganization. Both central fluid percussion TBI and combined TBI and bilateral entorhinal cortical lesion were examined. At 7 days survival, differential display, RT-PCR, and Northern blot analysis of hippocampal RNA from both TBI and combined insult models showed a significant induction of COII mRNA. This long-term elevation in COII gene expression was supported by increases in COII immunobinding. By contrast, cytochrome oxidase histochemical activity within tissue sections from injured brains suggested a reduction of complex IV activity within the TBI cases, but not within animals subjected to the combined insult. These differences in cytochrome c oxidase activity were supported by in vitro assay of complex IV using cerebral cortical and hippocampal tissues. Our present results support the hypothesis that COII is selectively vulnerable to TBI and that COII differences may indicate the degree of metabolic dysfunction induced by different pathologies. Taken together, such data will better define the role of metabolic function in long-term recovery after TBI.

Postinjury Administration of [formula omitted]-Deprenyl Improves Cognitive Function and Enhances Neuroplasticity after Traumatic Brain Injury

The rat model of combined central fluid percussion traumatic brain injury (TBI) and bilateral entorhinal cortical lesion (BEC) produces profound, persistent cognitive deficits, sequelae associated with human TBI. In contrast to percussive TBI alone, this combined injury induces maladaptive hippocampal plasticity. Recent reports suggest a potential role for dopamine in CNS plasticity after trauma. We have examined the effect of the dopamine enhancer l-deprenyl on cognitive function and neuroplasticity following TBI. Rats received fluid percussion TBI, BEC alone, or combined TBI + BEC lesion and were treated once daily for 7 days with l-deprenyl, beginning 24 h after TBI alone and 15 min after BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl treatment. Cognitive performance was assessed on days 11–15 postinjury and brains from the same cases examined for dopamine β-hydroxylase immunoreactivity (DBH-IR) and acetylcholinesterase (AChE) histochemistry. Significant cognitive improvement relative to untreated injured cases was observed in both TBI groups following l-deprenyl treatment; however, no drug effects were seen with BEC alone. l-Deprenyl attenuated injury-induced loss in DBH-IR over CA1 and CA3 after TBI alone. However, after combined TBI + BEC, l-deprenyl was only effective in protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with l-deprenyl in both injury models. After TBI + BEC, l-deprenyl also increased AChE in the dentate molecular layer relative to untreated injured cases. These results suggest that dopaminergic/noradrenergic enhancement facilitates cognitive recovery after brain injury and that noradrenergic fiber integrity is correlated with enhanced synaptic plasticity in the injured hippocampus.

Defense and Veterans Head Injury Program: background and overview.

Traumatic brain injury (TBI) is the principal cause of death and disability for young Americans, with an estimated societal cost of over $39 billion per year. The Defense and Veterans Head Injury Program (DVHIP) represents a close collaboration among the Departments of Defense (DoD) and Veterans Affairs (DVA), the Brain Injury Association (BIA), and the International Brain Injury Association (IBIA). Its principal mission is to ensure that military and veteran patients with head injury receive TBI-specific evaluation, treatment, rehabilitation, and follow-up, while at the same time addressing the readiness mission of the military and helping to define optimal care for victims of TBI nationwide. Defense and Veterans Head Injury Program activities can be grouped into three broad classes: (1) TBI education, community service, and primary prevention projects; (2) combined TBI clinical treatment, rehabilitation, and clinical research projects; and (3) clinically linked TBI laboratory research projects. It is thus based on a prudent integration of clinical care and follow-up with programmatic clinical and clinically related laboratory research, TBI prevention, and education. This previously nonexistent clinical infrastructure now offers a valuable base for ongoing TBI clinical research.

Effect of initially limited resuscitation in a combined model of fluid-percussion brain injury and severe uncontrolled hemorrhagic shock.

Studies of isolated uncontrolled hemorrhage have indicated that initial limited resuscitation improves survival. Limited resuscitation has not been studied in combined traumatic brain injury and uncontrolled hemorrhage. In this study the authors evaluated the effects of limited resuscitation on outcome in combined fluid-percussion injury (FPI) and uncontrolled hemorrhage. Twenty-four swine weighing 17 to 24 kg each underwent FPI (3 atm) and hemorrhage to a mean arterial pressure (MAP) of 30 mm Hg in the presence of a 4-mm aortic tear. Group I (nine animals) was initially resuscitated to a goal MAP of 60 mm Hg; Group II (nine animals) was resuscitated to a goal MAP of 80 mm Hg; and Group III (control; six animals) was not resuscitated. After 60 minutes, the aortic hemorrhage was controlled and the animals were resuscitated to baseline physiological parameters and observed for 150 minutes. Mortality rates were 11%, 50%, and 100% for Groups I, II, and III, respectively (Fisher's exact test; p = 0.002). The total hemorrhage volume was greater in Group II (69+/-32 ml/kg), as compared with Group I (41+/-18 ml/kg) and Group III (37+/-3 ml/kg) according to analysis of variance (p < 0.05). In surviving animals, cerebral perfusion pressure, cerebral blood flow (CBF), cerebral venous O2 saturation (ScvO2), and cerebral metabolic rate of O2 did not differ among groups. Although CBF was approximately 50% of baseline during the period of limited resuscitation in Group I, ScvO2 remained greater than 60%, and arteriovenous O2 differences remained within normal limits. In this model of FPI and uncontrolled hemorrhage, early aggressive resuscitation, which is currently recommended, resulted in increased hemorrhage and failure to optimize cerebrovascular parameters. In addition, a 60-minute period of moderate hypotension (MAP = 60 mm Hg) was well tolerated and did not compromise cerebrovascular hemodynamics, as evidenced by physiological parameters that remained within the limits of cerebral autoregulation.

Effects of ethanol in an experimental model of combined traumatic brain injury and hemorrhagic shock.

Given that clinical and laboratory studies suggest that ethanol and hemorrhagic shock (HS) potentiate traumatic brain injury (TBI), the authors studied the effects of ethanol in a model of combined TBI and HS. A controlled porcine model of combined TBI and HS was evaluated for the effect of ethanol on survival time, hemodynamic function, and cerebral tissue perfusion. Anesthetized swine (17-24 kg) were instrumented, splenectomized, and subjected to fluid percussion TBI with concurrent 25-mL/kg graded hemorrhage over 30 minutes. Two groups were studied: control (n = 11) and ethanol (n = 11). Ethanol, 3.5 g/kg intragastric, was given 100 minutes prior to TBI/HS. Systemic and cerebral physiologic and metabolic parameters were monitored for 2 hours without resuscitation. Regional cerebral blood flow (rCBF) and renal blood flow were measured with dye-labeled microspheres. Data were analyzed with 2-sample t-test and repeated-measures ANOVA. Ethanol levels at the time of injury were 162 +/- 68 mg/dL. Average TBI was 2.65 +/- 0.35 atm. Survival time was significantly shorter in the ethanol group (60 +/- 27 min vs 94 +/- 28 min, p = 0.011). The ethanol group had significantly lower mean arterial pressure, cerebral perfusion pressure, and cerebral venous O2 saturation in the postinjury period. Cerebral O2 extraction ratios and cerebral venous lactate levels were significantly higher in the ethanol group. A trend toward lower postinjury rCBF in all brain regions was observed in the ethanol group. In this TBI/HS model, ethanol administration decreased survival time, impaired the hemodynamic response, and worsened measures of cerebral tissue perfusion.

Traumatic brain injury, hemorrhagic shock, and fluid resuscitation: effects on intracranial pressure and brain compliance

Intracranial hypertension following traumatic brain injury is associated with considerable morbidity and mortality. Hemorrhagic hypovolemia commonly coexists with head injury in this population of patients. Therapy directed at correcting hypovolemic shock includes vigorous volume expansion with crystalloid solutions. It is hypothesized that, following traumatic brain injury, cerebrovascular dysfunction results in rapid loss of brain compliance, resulting in increased sensitivity to cerebrovascular venous pressure. Increased central venous pressure (CVP) occurring with vigorous crystalloid resuscitation may therefore contribute to the loss of brain compliance and the development of intracranial hypertension. The authors tested this hypothesis in miniature swine subjected to traumatic brain injury, hemorrhage, and resuscitation. Elevated CVP following resuscitation from hemorrhage to a high CVP significantly worsened intracranial hypertension in animals with concurrent traumatic brain injury, as compared to animals subjected to traumatic brain injury alone (mean +/- standard error of the mean: 33.0 +/- 2.0 vs. 20.0 +/- 2.0 mm Hg, p < 0.05) or to animals subjected to the combination of traumatic brain injury, hemorrhage, and resuscitation to a low CVP (33.0 +/- 2.0 vs. 24.0 +/- 2.0 mm Hg, p < 0.05). These data support the hypothesis that reduction in brain compliance can occur secondary to elevation of CVP following resuscitation from hemorrhagic shock. This may worsen intracranial hypertension in patients with traumatic brain injury and hemorrhagic shock.