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Donald W Marion

Publications and source records attributed to Donald W Marion.

At least 19 recordsLinked to original sources
PubMed2006

Proteolysis consistent with activation of caspase-7 after severe traumatic brain injury in humans.

The expression and proteolysis of caspase family proteins are involved in the initiation and execution of apoptosis, which has been reported to occur in human and experimental traumatic brain injury (TBI). Caspase-3, -6, and -7 belong to the group of executioner caspases, which are cleaved and activated at the late, irreversible stage of apoptosis. Our previous studies demonstrated roles for caspase-1, -3, and -8 in humans after severe TBI. Here we report expression of caspase-7 mRNA and protein in humans after TBI (n = 16) and control brain-bank tissue (n = 6). Semiquantitative reverse transcription polymerase chain reaction showed no differences between caspase-7 mRNA in TBI patients versus controls (73 +/- 24 vs. 85 +/- 56 relative optical density [ROD], respectively). In contrast, Western blot analysis showed increased pro-caspase-7 in TBI patients versus controls (214 +/- 30 vs. 1 +/- 1 ROD, respectively), as well as an increase in the approximately 20 kD proteolytic fragment in TBI patients versus controls (86 +/- 13 vs. 22 +/- 12 ROD, respectively), consistent with activation of caspase-7 after TBI in humans. Immunohistochemical analysis showed that cells expressing caspase-7 included astrocytes and neurons and possibly other glial cell types and infiltrated inflammatory cells. These data show that caspase-7 and its cleavage product are increased in human brain after TBI in many central nervous system, as well as noncentral nervous system, cell types. Thus, caspase-7 may play a role in the glial and inflammatory responses, and possibly neuronal death, after TBI in humans.

Apoptosis↗
PubMed2006

Evidenced-based guidelines for traumatic brain injuries.

An enormous amount of clinical and basic science brain injury research has been undertaken during the last several decades in an effort to improve outcomes following severe traumatic brain injury, but to date there still are no new therapies that have been clearly shown to be beneficial. There is, however, increasing evidence to suggest that evidence-based, protocol-driven, acute care can lead to improved outcomes. Evidence based guidelines for the medical and surgical management of severe brain injury, and for penetrating and pediatric brain injury, as well as for the pre-hospital management of brain injury, have all been published. In this chapter the conclusions of those guidelines is reviewed. In addition, the studies that demonstrate improved outcomes as a result of implementation of the guidelines are summarized.

Brain Injuries↗
PubMed2005

Increased phosphorylation of protein kinase B and related substrates after traumatic brain injury in humans and rats.

Activation of protein kinase B (PKB, also known as Akt) by phosphorylation at serine-473 and threonine-308 promotes cell survival in multiple in vitro and in vivo models where neuronal death is seen, including traumatic brain injury (TBI); however, whether PKB is activated in humans after TBI was heretofore unknown. Activated PKB inhibits apoptogenic factors and is involved in the regulation of several transcription factors. Accordingly, we examined phosphorylation of the PKB signaling pathway in humans as well as rats after TBI using phosphospecific antibodies. Increased phosphorylation of PKB and PKB substrates was detected in injured brain from both humans and rats. In humans, increased phosphorylation of the PKB signaling pathway-related proteins Bad and forkhead transcription factor (FKHR) was detected in patients with TBI versus controls. In rats, increased phosphorylation of FKHR, inhibitor of kappaBalpha, and cyclic adenosine monophosphate responsive element binding protein (CREB) was detected after TBI versus controls. The deoxyribonucleic acid-binding activity of CREB was also enhanced after TBI in rats. Increased phosphorylation of PKB and PKB substrates was identified in neurons and other cell types by immunohistochemistry in both humans and rats. These data show increased phosphorylation of PKB, PKB substrates, and related proteins after both experimental and clinical TBI, suggesting either activation of the PKB signaling pathway or reduced phosphatase activity in both species.

Adult↗
PubMed2005

Early Glasgow Outcome Scale scores predict long-term functional outcome in patients with severe traumatic brain injury.

Patients sustaining severe traumatic brain injury (TBI) have variable long-term outcomes. We examined the association between Glasgow Outcome Scale (GOS) assessed at 3 months and long-term outcomes at 12 months after TBI. We studied 159 patients with severe, closed traumatic brain injuries (Glasgow Coma Scale [GCS] <or= 8) who were treated at an academic medical center and survived for a minimum of 3 months after TBI. Demographics and admission clinical data and GOS at 3 and 12 months were analyzed. Multivariate logistic regression was used to asses the relationship between 3-month GOS, demographics, and clinical data and a poor outcome, defined as GOS 1-3 assessed at 12 months after injury. The patient population was predominantly male (77%), with a median age of 30 years and a median admission GCS of 6. The logistic regression model showed that the GOS at 3 months was the best predictor of 12-month outcomes (odds ratio = 15.22, p < 0.001). The presence of prolonged hypotension, diffuse axonal injury (DAI), and fixed and dilated pupils on admission were also significant independent predictors of poor 12-month outcome (for all, p <or= 0.047). The adjusted logistic model showed a steep gradient of long-term recovery potential depending upon GOS at 3 months, ranging from an 89.4% chance of poor outcome for patients with a GOS of 2, to a 0.11% chance of poor outcome for those with a GOS of 5. The 3-month GOS is a powerful independent predictor of long-term outcome for patients with severe TBI. Prolonged hypotension, DAI, and the presence of fixed and dilated pupils were also independent predictors of poor outcome.

Adolescent↗
PubMed2005

Gender associations with cerebrospinal fluid glutamate and lactate/pyruvate levels after severe traumatic brain injury.

OBJECTIVE: Female sex hormones appear to be neuroprotective after traumatic brain injury by attenuating multiple mechanisms of secondary insult, including excitotoxicity and ischemia. The purpose of this study was to evaluate associations between gender and cerebrospinal fluid glutamate and lactate/pyruvate production and the role of hypothermia with gender in attenuating these markers. DESIGN: Prospectively collected data were analyzed for adult patients with severe traumatic brain injury. Gender comparisons for cerebrospinal fluid glutamate and lactate/pyruvate production were determined using ventricular samples obtained over the first 48 hrs postinjury. SETTING: University-based level I trauma center. PATIENTS: There were 123 patients, male n = 93 and female n = 30 (n = 686 cerebrospinal fluid samples), with severe traumatic brain injury (Glasgow Coma Scale score < or =8). INTERVENTIONS: A portion of these patients were part of a randomized controlled trial evaluating the effect of (48 hrs) therapeutic hypothermia after severe traumatic brain injury. The remainder received hypothermia (24 hrs) if they met clinical care criteria. Patients were cooled to 32-33 degrees C (within approximately 8 hrs) for either 24 or 48 hrs and then were rewarmed or remained normothermic. MEASUREMENTS AND MAIN RESULTS: Regression analyses using generalized estimating equations for repeated measures showed significant increases in cerebrospinal fluid glutamate production for males compared with females (p = .0023) and a significant interaction between glutamate concentration, gender, and time (p = .0035) by 24 hrs postinjury. Females had lower lactate/pyruvate ratios than males (p = .0006), and there was a significant interaction between lactate/pyruvate, gender, and time (p = .0045) throughout the first 48 hrs postinjury. Hypothermia attenuated glutamate levels, particularly for males, over the time course studied. CONCLUSIONS: These data suggest significant gender differences with glutamate and lactate/pyruvate production after severe traumatic brain injury. Gender- and hormone-mediated differences in central nervous system pathophysiology should be considered with clinical trials in traumatic brain injury.

Adult↗
PubMed2004

Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury.

Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer's disease (AD). This immunohistochemical study determined the extent of AD-related changes in temporal cortex resected from individuals treated surgically for severe TBI. Antisera generated against Abeta species (total Abeta, Abeta(1-42), and Abeta(1-40)), the C-terminal of the Abeta precursor protein (APP), apolipoprotein E (apoE), and markers of neuron structure and degeneration (tau, ubiquitin, alpha-, beta-, and gamma-synuclein) were used to examine the extent of Abeta plaque deposition and neurodegenerative changes in 18 TBI subjects (ages 18-64 years). Diffuse cortical Abeta deposits were observed in one third of subjects (aged 35-62 years) as early as 2 h after injury, with only one (35-year old) individual exhibiting "mature", dense-cored plaques. Plaque-like deposits, neurons, glia, and axonal changes were also immunostained with APP and apoE antibodies. In plaque-positive cases, the only statistically significant change in cellular immunostaining was increased neuronal APP (P = 0.013). There was no significant correlation between the distribution of Abeta plaques and markers of neuronal degeneration. Diffuse tau immunostaining was localized to neuronal cell soma, axons or glial cells in a larger subset of individuals. Tau-positive, neurofibrillary tangle (NFT)-like changes were detected in only two subjects, both of more advanced age and who were without Abeta deposits. Other neurodegenerative changes, evidenced by ubiquitin- and synuclein-immunoreactive neurons, were abundant in the majority of cases. Our results demonstrate a differential distribution and course of intra- and extra-cellular AD-like changes during the acute phase following severe TBI in humans. Abeta plaques and early evidence of neuronal degenerative changes can develop rapidly after TBI, while fully developed NFTs most likely result from more chronic disease- or injury-related processes. These observations lend further support to the hypothesis that head trauma significantly increases the risk of developing pathological and clinical symptoms of AD, and provide insight into the molecular mechanisms that initiate these pathological cascades very early during severe brain injury.

Adolescent↗
PubMed2004

Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients.

Striking gender differences have been reported in the pathophysiology and outcome of acute neurological injury. Greater neuroprotection in females versus males may be due, in part, to direct and indirect sex hormone-mediated antioxidant mechanisms. Progesterone administration decreases brain levels of F(2)-isoprostane, a marker of lipid peroxidation, after experimental traumatic brain injury (TBI) in male rats, and estrogen is neuroprotective in experimental neurological injury. In this study, we evaluated the effect of gender on lipid peroxidation, as assessed by cerebrospinal fluid (CSF) levels of F(2)-isoprostane, after severe TBI in humans. Lipid peroxidation was assessed in CSF from 68 adults enrolled in two randomized controlled trials evaluating the effect of therapeutic hypothermia after severe TBI (Glasgow coma scale [GCS] score </= 8). Patients treated with hypothermia (n = 41, 12 females, 29 males) were cooled to 32-33 degrees C (within approximately 6 h) for either 24 or 48 h and then re-warmed. F(2)-isoprostane levels were assessed by ELISA in ventricular CSF samples (n = 199) on day 1, 2, and 3. The association between age, GCS score, time, gender, treatment, duration of treatment, core temperature at the time of CSF sampling, secondary hypoxemia, and CSF F(2)-isoprostane level was assessed by multivariate and dichotomous analyses. F(2)-isoprostane was approximately 2-fold higher in males than females (145.8 +/- 39.6 versus 75.4 +/- 16.6 pg/mL, day 1 p = 0.018). An effect of time after injury (p = 0.007) was reflected by a marked early peak in F(2)-isoprostane (day 1). CSF F(2)-isoprostane was also associated with hypoxemia (p = 0.04). Hypothermia tended to decrease F(2)-isoprostane levels only in males on d1 after TBI. To our knowledge, this is the first study showing gender differences in lipid peroxidation after clinical TBI. Lipid peroxidation occurs early after severe TBI in adults and is more prominent in males vs females. These results established that gender is an important consideration in clinical trial design, particularly in the case of antioxidant strategies.

Adult↗
PubMed2004

The effects of admission alcohol level on cerebral blood flow and outcomes after severe traumatic brain injury.

This study examined the relationship between admission serum alcohol level (ETOH) and cerebral blood flow (CBF) and outcomes in the adult traumatic brain injured (TBI) population. We hypothesized that individuals with ETOH > 100 mg/dL will have decreased blood flow on admission and poorer outcomes. Eighty subjects, age 16-65, with severe TBI (Glasgow Coma Score [GCS] </= 8) were entered into the study. Correlational analysis assessed the relationship between ETOH and admission severity of injury scores as measured by Marshall and APACHE III scores, CBF, and outcomes. Comparison of CBF and outcomes between groups based on admission serum ETOH level was conducted with analysis of variance and post hoc Scheffé analyses as well as regression analysis. There was a significant relationship between serum ETOH level and GCS (p = 0.02), but not APACHE III scores (p = 0.12) or Marshall scores (p = 0.27). There was a significant correlation between global CBF and serum ETOH level (p = 0.02). There was no statistically significant association between serum ETOH level and GOS at 3 (p = 0.97), 6 (p= 0.56), or 12 (p = 0.73) months after injury. The data indicated that serum ETOH levels > 100 mg/dL at the time of admission after a TBI were associated with a decrease in global CBF. Elevated serum ETOH level at time of injury did not, however, impact outcomes.

Adult↗
PubMed2004

Controlled normothermia in neurologic intensive care.

Preclinical studies of cerebral ischemia and trauma find increased brain tissue injury and worsened functional outcomes if the brain temperature exceeds 39 degrees C. Several retrospective studies of patients with new-onset stroke, intracerebral hemorrhage, or subarachnoid hemorrhage support these observations. However, fever is very common among these patients early after the onset of their disease, particularly if they are in the ICU for a week or more, and brain temperatures are likely to be as much as 2 degrees C higher than rectal temperatures. Finally, intravascular temperature modulation has been shown to be more effective for preventing fever than conventional methods, such as antipyretic medications or surface-cooling techniques. Further study is needed to establish if such better control of temperature will lead to improved outcomes.

Animals↗
PubMed2003

Caspase-8 expression and proteolysis in human brain after severe head injury.

Programmed cell death involves a complex and interrelated cascade of cysteine proteases termed caspases that are synthesized as inactive zymogens, which are proteolytically processed to active enzymes. Caspase-8 is an initiator caspase that becomes activated when Fas death receptor-Fas ligand (FasL) coupling on the cell surface leads to coalescence of a "death complex" perpetuating the programmed cell death cascade. In this study, brain tissue samples removed from adult patients during the surgical management of severe intracranial hypertension after traumatic brain injury (TBI; n=17) were compared with postmortem control brain tissue samples (n=6). Caspase-8 mRNA was measured by semiquantitative reverse transcription and polymerase chain reaction, and caspase-8 protein was examined by Western blot and immunocytochemistry. Fas and FasL were also examined using Western blot. Caspase-8 mRNA and protein were increased in TBI patients vs. controls, and caspase-8 protein was predominately expressed in neurons. Proteolysis of caspase-8 to 20-kDa fragments was seen only in TBI patients. Fas was also increased after TBI vs. control and was associated with relative levels of caspase-8, supporting formation of a death complex. These data identify additional steps in the programmed cell death cascade involving Fas death receptors and caspase-8 after TBI in humans.

Age Factors↗
PubMed2003

Alterations in inducible 72-kDa heat shock protein and the chaperone cofactor BAG-1 in human brain after head injury.

The stress response in injured brain is well characterized after experimental ischemic and traumatic brain injury (TBI); however, the induction and regulation of the stress response in humans after TBI remains largely undefined. Accordingly, we examined injured brain tissue from adult patients (n = 8) that underwent emergent surgical decompression after TBI, for alterations in the inducible 72-kDa heat shock protein (Hsp70), the constitutive 73-kDa heat shock protein (Hsc70), and isoforms of the chaperone cofactor BAG-1. Control samples (n = 6) were obtained postmortem from patients dying of causes unrelated to CNS trauma. Western blot analysis showed that Hsp70, but not Hsc70, was increased in patients after TBI versus controls. Both Hsp70 and Hsc70 coimmunoprecipitated with the cofactor BAG-1. The 33 and 46, but not the 50-kDa BAG-1 isoforms were increased in patients after TBI versus controls. The ratio of the 46/33-kDa isoforms was increased in TBI versus controls, suggesting negative modulation of Hsp70/Hsc70 protein refolding activity in injured brain. These data implicate induction of the stress response and its modulation by the chaperone cofactor and Bcl-2 family member BAG-1, after TBI in humans.

Adolescent↗
PubMed2003

Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats.

OBJECTIVES: To determine whether transient, moderate hypothermia is beneficial after traumatic brain injury in fentanyl-anesthetized rats. DESIGN: Prospective, randomized study. SETTING: University-based animal research facility. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: All rats were intubated, mechanically ventilated, and anesthetized with fentanyl (10 microg/kg intravenous bolus and then 50 microg.kg(-1).hr(-1) infusion). Controlled cortical impact was performed to the left parietal cortex, followed immediately by 1 hr of either normothermia (brain temperature 37 +/- 0.5 degrees C) or hypothermia (brain temperature 32 +/- 0.5 degrees C). Hypothermic rats were rewarmed gradually over 1 hr. Fentanyl anesthesia and mechanical ventilation were continued in both groups until the end of rewarming (2 hrs after traumatic brain injury). MEASUREMENTS AND MAIN RESULTS: Histologic assessment performed 72 hrs after traumatic brain injury was the primary outcome variable. Secondary outcome variables were physiologic variables monitored during the first 2 hrs after traumatic brain injury and plasma catecholamine and serum fentanyl concentrations measured at the end of both hypothermia and rewarming (1 and 2 hrs after traumatic brain injury). Contusion volume was larger in hypothermic vs. normothermic rats (44.3 +/- 4.2 vs. 28.6 +/- 4.0 mm, p <.05), but hippocampal neuronal survival did not differ between groups. Physiologic variables did not differ between groups. Plasma dopamine and norepinephrine concentrations were increased at the end of hypothermia in hypothermic (vs. normothermic) rats (p <.05), indicating that hypothermia augmented the systemic stress response. Similarly, serum fentanyl concentrations were higher in hypothermic (vs. normothermic) rats at the end of both hypothermia and rewarming (p <.05), demonstrating that hypothermia reduced the clearance and/or metabolism of fentanyl. CONCLUSIONS: Moderate hypothermia was detrimental after experimental traumatic brain injury in fentanyl-anesthetized rats. Since treatment with hypothermia has provided reliable benefit in experimental traumatic brain injury with inhalational anesthetics, these results indicate that the choice of anesthesia/analgesia after traumatic brain injury may dramatically influence response to other therapeutic interventions, such as hypothermia. Given that narcotics commonly are administered to patients after severe traumatic brain injury, this study may have clinical implications.

Anesthesia, Intravenous↗
PubMed2003

Relationship between apoE4 allele and excitatory amino acid levels after traumatic brain injury.

OBJECTIVE: Apolipoprotein E isoform (E4) has been posited to affect outcomes after central nervous system injury. This project sought to determine the relationship between the apoE4 allele and the recovery of amino acid neurotransmitters (aspartate, glutamate, and lactate/pyruvate ratio [L/P]) following a traumatic brain injury (TBI) after controlling for patient characteristics. DESIGN: This prospective clinical study examined neurotransmitters and L/P within the cerebrospinal fluid and compared the trends by apoE genotypes. SETTING: Adults with TBI were recruited from a neurotrauma intensive care unit within a trauma I university medical center. PATIENTS: Ninety-one patients were enrolled into the study after a severe TBI (Glasgow Coma Scale [GCS] score, </=8). Cerebrospinal fluid was serially sampled from a ventriculostomy every 4 hrs for the first 24 hrs and every 6 hrs for 25-120 hrs after injury. MEASUREMENTS AND MAIN RESULTS: Hierarchical linear modeling analyses were used to compare the change of glutamate, aspartate, and L/P over time by the presence or absence of the apoE4 allele, with GCS score, sex, race, and therapeutic hypothermias included as covariates. There was a significant apoE4 allele group effect on both the linear and quadratic slopes in aspartate. In glutamate, the rate of change in glutamate was statistically related to GCS score. There was no significant difference in the glutamate response over time by the presence of the apoE4 allele. There was a significant difference in the change in L/P across time, with faster recovery when the apoE4 allele was absent. CONCLUSIONS: Recovery of aspartate and L/P differed depending on the presence of the apoE4 allele. Patients with the allele had significant increased and sustained levels of aspartate and L/P after TBI. Changes in glutamate were related to severity of illness and were independent of the presence of the apoE4 allele.

Adolescent↗
PubMed2003

Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury.

OBJECTIVE: To test the hypothesis that etomidate treatment improves functional, cognitive, and histologic outcome after experimental traumatic brain injury. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Traumatic brain injury was produced by controlled cortical impact injury (4 m/sec, 2.6 mm of tissue deformation). Etomidate (2 mg/kg) was administered intravenously immediately before injury (n = 13) or 5 mins after injury (n = 12). Additional rats received saline treatment 5 mins after injury (n = 12) or served as sham controls (n = 10). MEASUREMENTS AND MAIN RESULTS: Rats were evaluated on beam balance and beam walk tasks on postoperative days 1-5 and then trained in the Morris water maze on postoperative days 14-18. On day 28, the rats were killed, and hippocampal CA1 and CA3 neuron counts and cortical lesion volume were measured in histologic brain sections. Preinjury etomidate attenuated beam balance deficits, water maze deficits, hippocampal CA3 neuronal loss, and cortical tissue loss but did not attenuate beam walk deficits or hippocampal CA1 neuronal loss. Postinjury etomidate attenuated water maze deficits, but it did not affect any other outcome measure. CONCLUSIONS: Administration of etomidate both before and after injury attenuates secondary injury resulting from traumatic brain injury, but the effect is more pronounced with pretreatment. The ineffectiveness of postinjury etomidate on motor and histologic tasks suggests a brief therapeutic treatment window in rats. However, the treatment window in humans is unknown. Lastly, postinjury etomidate did not exacerbate neurologic or histologic outcome.

Animals↗
PubMed2003

Physical medicine and rehabilitation consultation: relationships with acute functional outcome, length of stay, and discharge planning after traumatic brain injury.

OBJECTIVE: Patients hospitalized with traumatic brain injury comprise a large portion of the population treated at trauma centers, and physiatry consultants evaluate many traumatic brain injury patients in this setting. The purpose of this study was to delineate relationships between physical medicine and rehabilitation consultation in this population and acute functional outcome, length of stay, and discharge planning. DESIGN: Data were obtained for 1866 adult patients hospitalized with nonfatal traumatic brain injury. Functional outcome was determined using a modification of the FIM trade mark. Descriptive and regression analyses were used to determine the relationship of physical medicine and rehabilitation consultation to acute discharge FIM score, length of stay, and discharge disposition. RESULTS: Patients receiving physical medicine and rehabilitation consultation had more severe injuries, lower acute discharge FIM scores, and longer length of stay. However, multivariate analysis showed that earlier (<48 hr after admission) physical medicine and rehabilitation consultation resulted in significantly better FIM scores with transfers (odds ratio, 2.61; 95% confidence interval, 1.06-6.40) and locomotion (odds ratio, 3.54; 95% confidence interval, 1.34-9.32) and a significantly shorter acute length of stay (P = 0.001). CONCLUSIONS: Early physical medicine and rehabilitation consultation may positively impact functional status and length of stay for patients with traumatic brain injury during acute hospitalization. Additional work is needed to determine how physical medicine and rehabilitation consultation impacts rehabilitation-specific medical issues, long-term functional outcome, and healthcare costs.

Adult↗
PubMed2002

Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury.

Increases in brain interstitial excitatory amino acid (EAA(I)) concentrations after ischemia are ameliorated by use-dependent Na+ channel antagonists and by supplementing interstitial glucose, but the regulation of EAA(I) after traumatic brain injury (TBI) is unknown. We studied the regulation of EAA(I) after TBI using the controlled cortical impact model in rats. To monitor changes in EAA(I), microdialysis probes were placed in the cortex adjacent to the contusion and in the ipsilateral hippocampus. Significant increases in dialysate EAA(I) after TBI were found compared to levels measured in sham controls. Treatment with the use-dependent Na+ channel antagonist 619C89 (30 mg/kg i.v.) did not significantly decrease dialysate glutamate compared to vehicle controls in hippocampus (10.4+/-2.4 vs. 11.9+/-1.6 microM), but there was significant decrease in dialysate glutamate in cortex after 619C89 treatment (19.3+/-3 vs. 12.6+/-1.1 microM, P<0.05). Addition of 30 mM glucose to the dialysate, a treatment that decreases EAA(I) after ischemia, had no significant effect upon dialysate glutamate after TBI in cortex (20.0+/-4.9 vs. 11.7+/-3.4 microM) or in hippocampus (10.9+/-2.0 vs. 8.9+/-2.4 microM). These results suggest that neither increased release of EAAs due to Na+ channel-mediated depolarization nor failure of glutamate reuptake due to glucose deprivation can explain the majority of the increase in EAA(I) following TBI.

Animals↗
PubMed2002

Acute systemic administration of interleukin-10 suppresses the beneficial effects of moderate hypothermia following traumatic brain injury in rats.

Traumatic injury to the central nervous system initiates inflammatory processes such as the synthesis of proinflammatory mediators that contribute to secondary tissue damage. Hence, administration of anti-inflammatory cytokines, such as interleukin-10 (IL-10) may be neuroprotective. Moderate hypothermia (30-32 degrees C) also decreases the pro-inflammatory response to traumatic brain injury (TBI). Thus, we hypothesized that the combination of IL-10 and hypothermia would provide synergistic neuroprotective effects after TBI. To test this hypothesis, fifty isoflurane-anesthetized rats underwent a controlled cortical impact (2.7 mm tissue deformation at 4 m/s) or sham injury and then were randomly assigned to one of five conditions (TBI/VEH Normothermia (37 degrees C), TBI/VEH Hypothermia (32 degrees C for 3 h), TBI/IL-10 Normothermia, TBI/IL-10 Hypothermia, and Sham/VEH Normothermia). Human IL-10 (5 microg) or VEH was administered (i.p.) 30 min after surgery. Function was assessed by established motor and cognitive tests on post-operative days 1-5 and 14-18, respectively. Cortical lesion volume and hippocampal CA(1)/CA(3) cell survival were quantified at 4 weeks. Brain sections from 15 additional rats were immunohistochemically assessed (MoAB RP-3) to determine neutrophil accumulation at 5 h after TBI. The administration of IL-10 after TBI produced an approximately 75% reduction in the number of RP-3-positive cells in both the normothermic and hypothermic groups vs. the normothermic vehicle-treated group (P<0.05), but did not improve functional outcome. In contrast, hypothermia alone enhanced both motor and cognitive function and increased CA(3) neuronal survival after TBI. Contrary to our hypothesis, systemic administration of IL-10 combined with hypothermia did not provide synergistic neuroprotective effects after TBI. Rather, IL-10 administration suppressed the beneficial effects produced by hypothermia alone after TBI. The mechanism(s) for the negative effects of IL-10 combined with hypothermia after TBI remain to be determined.

Animals↗