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Objective: The role of autophagy in moderate hypothermia in posttraumatic brain injury (post-TBI) remains elusive. In this study, we evaluated the protective role of autophagy in post-TBI moderate hypothermia., Methods: Adult male Sprague-Dawley rats were randomly divided into 3 groups (n = 36/group): TBI with hypothermia group (sham), TBI with hypothermia and a single intracerebroventricular injection of saline (saline, 5 μL), and TBI with hypothermia and a single intracerebroventricular injection of 3-methyladenine (600 nmol, diluted in 0.9% saline to a final volume of 5 μL). All rats, except those in the behavioral tests, were killed at 24 hours after fluid percussion TBI. Immunohistochemistry staining, western blot, and transmission electron microscopy were performed to assess changes in apoptosis and autophagy after injection of 3-methyladenine. Motor function (beam-walk test) and spatial learning/memory (Morris water maze) were assessed on postoperative days 1-5 and 11-15, respectively., Results: Our results showed downregulation of the expression level of microtubule-associated protein 1 light chain 3 and Beclin-1, aggravation of behavioral outcome, and increase of apoptosis., Conclusion: Our results suggest that the autophagy pathway is involved in the neuroprotective effect of post-TBI hypothermia and negative modulation of apoptosis may be 1 possible mechanism., (Copyright © 2016. Published by Elsevier Inc.)

Traumatic brain injury (TBI) treatment is a long-term process and requires repeated medicine administration, which, however, can cause high expense, infection, and hemorrhage to patients. To investigate how a long-term expression of nerve growth factor (Ngf) gene affects the injured hippocampus function post-TBI, in this study, a pseudo lentivirus carrying the β-Ngf fusion gene, with green fluorescence protein (GFP) gene, was constructed to show the gene expression and its ability of protecting cells from oxidative damage in vitro. Then, the pseudo lentivirus-carried β-Ngf fusion gene was directly injected into the injured brain to evaluate its influence on the injured hippocampus function post-TBI in vivo. We found that the expression of the pseudo lentivirus-delivered β-Ngf fusion gene lasted more than four-week after the cell transduction and the encoded β-NGF fusion protein could induce the neuron-like PC12 cell differentiation. Moreover, the hippocampal injection of the pseudo lentivirus-carried β-Ngf fusion gene sped the injured cognitive function recovery of the rat subjected to TBI. Together, our findings indicate that the long-term expression of the β-Ngf fusion gene, delivered by the pseudo lentivirus, can promote the neurite outgrowth of the neuron-like cells and protect the cells from the oxidative damage in vitro, and that the direct and single dose hippocampal injection of the pseudo lentivirus-carried β-Ngf fusion gene is able to rescue the hippocampus function after the TBI in the rat., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Multiple mechanisms participated in the cell death after fluid percussion traumatic brain injury (TBI). In the present study, we evaluated the effect on cell death in the injured cortex after fluid percussion TBI and investigated a possible role of autophagy., Methods: TBI model was induced by a fluid percussion TBI device. Moderate hypothermia (32°C) was achieved by partial immersion in a water bath (0°C) under general anesthesia for 4 hours. All rats were killed at 6 or 24 hours after TBI., Results: Cleaved caspase 3 evaluated with Western blotting and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling-positive cells in injured cortex were significantly increased 6 hours after fluid percussion TBI and were further up-regulated 24 hours after TBI, dramatic up-regulation of Beclin-1 and protein light chain-3 expression levels was also observed. Further up-regulation of biomarkers of autophagy, attenuation of caspase 3 up-regulation and reduction of cell death was observed after 4 hours of hypothermia. Immunofluorescence analysis for cell localization demonstrated that protein light chain-3- and Beclin-1-positive cells included neurons and glial cells in the injured cortex after TBI and hypothermic treatment. By ultrastructural observation, autolysosomes in injured cortex were significantly increased at 6 and 24 hours after TBI and were further up-regulated after TBI hypothermic treatment., Conclusions: These data suggest that hypothermic treatment could attenuate TBI-induced cell death in this fluid percussion TBI model, possibly through activation of autophagy pathway., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Here, we evaluated changes in autophagy after post-traumatic brain injury (TBI) followed by moderate hypothermia in rats. Adult male Sprague-Dawley rats were randomly divided into four groups: sham injury with normothermia group (37 °C); sham injury with hypothermia group (32 °C); TBI with normothermia group (TNG; 37 °C); and TBI with hypothermia group (THG; 32 °C). Injury was induced by a fluid percussion TBI device. Moderate hypothermia (32 °C) was achieved by partial immersion in a water bath (0 °C) under general anesthesia for 4 h. All rats were killed at 24 h after fluid percussion TBI. The ipsilateral hippocampus in all rats was analyzed with hematoxylin and eosin staining; terminal deoxynucleoitidyl transferase-mediated nick end labeling staining was used to determine cell death in ipsilateral hippocampus. Immunohistochemistry and western blotting of microtubule-associated protein light chain 3 (LC3), Beclin-1, as well as transmission electron microscopy performed to assess changes in autophagy. At 24 h after TBI, the cell death index was 27.90 ± 2.36% in TNG and 14.90 ± 1.52% in THG. Expression level of LC3 and Beclin-1 were significantly increased after TBI and were further up-regulated after post-TBI hypothermia. Further, ultrastructural observations showed that there was a marked increase of autophagosomes and autolysosomes in ipsilateral hippocampus after post-TBI hypothermia. Our data demonstrated that moderate hypothermia significantly attenuated cell death and increased autophagy in ipsilateral hippocampus after fluid percussion TBI. In conclusion, autophagy pathway may participate in the neuroprotective effect of post-TBI hypothermia.

Programmed necrosis or necroptosis is an alternative form of cell death that is executed through a caspase-independent pathway. Necroptosis has been implicated in many pathological conditions. Genetic or pharmacological inhibition of necroptotic signaling has been shown to confer neuroprotection after traumatic and ischemic brain injury. Therefore, the necroptotic pathway represents a potential target for neurological diseases that are managed by neurosurgeons. In this review, we summarize recent advances in the understanding of necroptotic signaling pathways and explore the role of necroptotic cell death in craniocerebral trauma, brain tumors, and cerebrovascular diseases.

The aim of this study was to evaluate the potential efficacy of SB-3CT, a matrix metallopeptidase 9 inhibitor, on behavioral and histological outcomes after traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were randomly divided into three groups (n=15/group): TBI with SB-3CT treatment, TBI with saline, and sham injury. The TBI model was induced by a fluid percussion TBI device. SB-3CT (50 mg/kg in 10% dimethyl sulfoxide) was administered intraperitoneally at 30 min, 6 h, and 12 h after the TBI. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative Days 1-5 and 11-15, respectively. Fluoro-Jade staining, immunofluorescence, and cresyl violet-staining were carried out for histopathological evaluation at 24 h, 72 h, and 15 days after TBI, respectively. It was shown that TBI can result in significant behavioral deficit induced by acute neurodegeneration, increased expression of cleaved caspase-3, and long-term neuronal loss. SB-3CT intervention via the current regime provides robust behavioral protection and hippocampal neurons preservation from the deleterious effects of TBI. Hence, the efficacy of SB-3CT on TBI prognosis could be ascertained. It is believed that the current study adds to the growing literature in identifying SB-3CT as a potential therapy for human brain injury.

Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Nav1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Nav1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Nav1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Nav1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Nav1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Nav1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Nav1.3 expression in the brain may improve outcomes following TBI.

Here we investigate the effect of hypothermia on the expression of apoptosis-regulating protein TIMP-3 after fluid percussion traumatic brain injury (TBI) in rats. We began with 210 adult male Sprague-Dawley rats and randomly assigned them to three groups: TBI with hypothermia treatment (32°C), TBI with normothermia (37°C), and sham-injured controls. TBI was induced by a fluid percussion TBI device. Mild hypothermia (32°C) was achieved by partial immersion in a water bath (0°C) under general anesthesia for 4 h. The rats were killed at 4, 6, 12, 24, 48, and 72 h and 1 week after TBI. The mRNA and protein level of TIMP-3 in both the injured and uninjured hemispheres of the brains from each group were measured using RT-PCR and Western blotting. In the normothermic group, TIMP-3 levels in both the injured and uninjured hemispheres were significantly increased after TBI compared with those of sham-injured animals (p < 0.01). In contrast, post-traumatic hypothermia significantly attenuated this increase. According to the RT-PCR and Western blot analyses, the maximum mRNA levels of TIMP-3 were reduced to 60.60 ± 2.30%, 55.83 ± 1.80%, 66.03 ± 2.10%, and 64.51 ± 1.50%, respectively, of the corresponding values in the normothermic group in the injured and uninjured hemispheres (cortex and hippocampus) of the hypothermia group (p < 0.01), while the respective maximum protein levels of TIMP-3 were reduced to 57.50 ± 1.50, 52.67 ± 2.20, 60.31 ± 2.50 and 54.76 ± 1.40 (p < 0.01). Our data suggest that moderate fluid percussion brain injury significantly upregulates TIMP-3 expression, and that this increase may be suppressed by hypothermia treatment.

Objective: The Chinese Head Trauma Data Bank (CHTDB) has been established, which includes 7,145 hospitalised cases with acute head trauma patients in 47 hospitals., Methods: We explored factors that might affect the outcome of acute traumatic brain injury., Results: There was no statistical difference in the mortality rate between male (7.5%) and female (7.2%) patients (P>0.05). The mortality rate in children (<18 years), adults (18-65 years) and elderly (>65 years) was 7.3%, 7.2% and 9.0%, respectively (P>0.05). The mortality rate of patients with mild (2.7%), moderate (5.0%) and severe (21.8%) head trauma was significantly different (P<0.001). The mortality rate of patients with unilateral tentorial herniation, bilateral tentorial herniation and tonsillar herniation was 24.2%, 60.2% and 78.8% respectively (P<0.001). The mortality rate of patients with intracranial pressure (ICP)<20 mm Hg, 20-40 mm Hg and >40 mm Hg was 6.3%, 21.4% and 93.1%, respectively (P<0.001). The mortality rate of patients with no cerebral contusion, single cerebral contusion and multiple cerebral contusions was 3.9%, 7.8% and 14.8%, respectively (P<0.001). The mortality rate of patients with and without traumatic subarachnoid haemorrhage (tSAH) was 9.5% and 5.4%, respectively (P<0.001). The mortality rate of patients with no intracranial haematomas, single intracranial haematoma and multiple intracranial haematomas was 5.8%, 8.4% and 20.6%, respectively (P<0.001)., Conclusion: The CHTDB, the first head trauma data bank in China, has one of the largest numbers of cases of any head trauma data bank in the world. Our major findings on mortality may be helpful to neurosurgeons for predicting the outcome of acute head trauma patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

During the secondary injury period after traumatic brain injury (TBI), depolarization of neurons mediated by voltage-gated sodium channels (VGSCs) leads to cellular abnormalities and neurological dysfunction. Alterations in expression of different α subunits of VGSCs can affect early brain pathology following TBI. This study detected the expression of Nav1.3 mRNA and protein in the rat cortex post-TBI. Adult male Sprague-Dawley rats were randomly assigned to sham-TBI, mild-TBI (mTBI), or severe-TBI (sTBI) groups. TBI was induced using a fluid percussion device at magnitudes of 1.5-1.6 atm (mTBI) and 2.9-3.0 atm (sTBI). Nav1.3 mRNA and protein levels in the ipsilateral-injured cortex were examined at 2 h, 12 h, 24 h, and 72 h post-TBI by real-time reverse transcriptase quantitative polymerase chain reaction and Western blot. Brains were collected at 24 h, 72 h, and 7 days post-TBI for TUNEL staining and cell count analysis. Immunofluorescence was performed to localize expression of Nav1.3 protein in the ipsilateral-injured cortex. Expression of Nav1.3 mRNA and protein were significantly upregulated in mTBI and sTBI groups when compared with the sham-TBI group at 2 h and 12 h post-TBI. Nav1.3 mRNA and protein levels in the sTBI group were much higher than in the mTBI group at 12 h post-TBI. TUNEL-positive cell numbers were significantly higher in the sTBI group than in the mTBI at 24 h, 72 h, and 7 days post-TBI. Expression of Nav1.3 was observed predominantly in neurons of the cortex. These findings indicated significant upregulation in the expression of Nav1.3 mRNA and protein in the rat ipsilateral-injured cortex at the very early stage post-TBI, and were also correlated with TBI severity.

The blood-brain barrier (BBB) opening following traumatic brain injury (TBI) provides a chance for therapeutic agents to cross the barrier, yet the reduction of the cerebral microvascular perfusion after TBI may limit the intervention. Meanwhile, optimizing the cerebral capillary perfusion by the strategies such as fluid administration may cause brain edema due to the BBB opening post trauma. To guide the TBI therapy, we characterized the relationship between the changes in the cerebral capillary perfusion and BBB permeability after TBI. First, we observed the changes of the cerebral capillary perfusion by the intracardiac perfusion of Evans Blue and the BBB disruption with magnetic resonance imaging (MRI) in the rat subjected to lateral fluid percussion (FP) brain injury. The correlation between two variables was next evaluated with the correlation analysis. Since related to BBB breakdown, matrix metalloproteinase-9 (MMP-9) activity was finally detected by gelatin zymography. We found that the ratios of the perfused microvessel numbers in the lesioned cortices were significantly reduced at 0 and 1 h post trauma compared with that in the normal cortex, which then dramatically recovered at 4 and 24 h after injury, and that the BBB permeability was greatly augmented in the ipsilateral parts at 4, 12, and 24 h, and in the contralateral area at 24 h after injury compared with that in the uninjured brain. The correlation analysis showed that the BBB permeability increase was related to the restoration of the cerebral capillary perfusion over a 24-h period post trauma. Moreover, the gelatin zymography analysis indicated that the MMP-9 activity in the injured brain increased at 4 h and significantly elevated at 12 and 24 h as compared to that at 0 or 1 h after TBI. Our findings demonstrate that the 4 h post trauma is a critical turning point during the development of TBI, and, importantly, the correlation analysis may guide us how to treat TBI.

Poly(n-butyl-2-cyanoacrylate) (PBCA) nanoparticles have been successfully applied to deliver small-molecule drugs to the central nervous system (CNS). However, it is unclear whether PBCA nanoparticles can be used as the delivery system for large molecules to potentially treat traumatic brain injury (TBI). In this study, we tested the capacity of PBCA nanoparticles in passing through the blood-brain barrier (BBB) and transporting large molecules into normal and injured brains in the rat. We first synthesized PBCA nanoparticles by dispersion polymerization and then loaded the particles with either horseradish peroxidase (HRP, 44 kDa) or enhanced green fluorescent protein (EGFP, 29 kDa), which were further coated with polysorbate 80. Next, the polysorbate 80-coated HRP or EGFP-loaded PBCA nanoparticles were intravenously injected into the normal and brain-injured rats. We found that, at 45 min after injection, PBCA nanoparticle-delivered HRP or EGFP was hardly detected in the normal brains of the rats, but a small amount of EGFP carried by PBCA nanoparticles was noted in the normal brains 48 h after administration, which was further confirmed by immunolocalization with anti-EGFP antibodies. In contrast, at 4 h after TBI with a circulation time of 45 min, although the penetration of HRP or EGFP alone was hampered by the BBB, the PBCA nanoparticle-delivered HRP or EGFP was widely distributed near injured sites. Together, our findings provide histological evidence that PBCA nanoparticles can be used as an efficient delivery system for large molecules to overcome the barrier in the brain with TBI.

Objective: To evaluate all the possible therapeutic measures concerning the acute management of traumatic brain injury (TBI) mentioned in Cochrane Systematic Reviews published in the Cochrane Database of Systematic Reviews (CDSR)., Methods: An exhausted literature search for all published Cochrane Systematic Reviews discussing therapeutic rather than prevention or rehabilitative interventions of TBI was conducted. We retrieved such databases as CDSR and Cochrane Injury Group, excluded the duplications, and eventually obtained 20 results, which stand for critical appraisal for as many as 20 different measures for TBI patients. The important data of each systematic review, including total population, intervention, outcome, etc, were collected and presented in a designed table. Besides, we also tried to find out the possible weakness of these clinical trials included in each review., Results: Analysis of these reviews yielded meanfuling observations: (1) The effectiveness of most ordinary treatments in TBI is inconclusive except that corticosteroids are likely to be ineffective or harmful, and tranexamic acid, nimodipine and progesterone show a promising effect in bleeding trauma, traumatic subarachnoid hemorrhage, TBI or severe TBI. (2) A majority of the systematic reviews include a small number of clinical trials and the modest numbers of patients, largely due to the uncertainty of the effectiveness. (3) The quality of most trials reported in the systematic reviews is more or less questionable. (4) In addition, lots of other complex factors together may lead to the inconclusive results demonstrated in the Cochrane Systematic Reviews., Conclusions: For clinical physicians, to translate these conclusions into practice with caution is essential. Basic medication and nursing care deserve additional attention as well and can be beneficial. For researchers, high quality trials with perfect design and comprehensive consideration of various factors are urgently required.

Hyperthermia may accentuate the detrimental consequences of brain injury and worsen the outcome of patients with acute head trauma, especially severe traumatic brain injury (TBI). We explored the effect of different magnitudes and durations of hyperthermia in the first 3 days after injury on the outcome of 7145 patients with acute head trauma, including 1626 with severe TBI. The differences in mortality and unfavorable outcome between the normothermia group, mild fever group, moderate fever group, and high fever group were statistically significant (p<0.001). The mortality and unfavorable outcome of severe TBI patients in the groups also differed significantly (p<0.001). The mortality and unfavorable outcome of patients with 1 day, 2 days, and 3 days of high fever were significantly increased (p<0.01). Our data strongly indicate that both degree and duration of early post-trauma hyperthermia are closely correlated with the outcome of acute TBI patients, especially severely injured ones, which indicates that hyperthermia may play a detrimental role in the delayed mechanisms of damage after acute TBI. Prevention of early hyperthermia after acute head trauma is therefore essential to the management of TBI patients.

Background: Traumatic brain injury (TBI), a major cause of morbidity and mortality, is a serious public health concern., Objective: To evaluate the effect of mild hypothermia on gene expression in the hippocampus and to try to elucidate molecular mechanisms of hypothermic neuroprotection after TBI., Methods: Rats were subjected to mild hypothermia (group 1: n = 3, 33 degrees C, 3H) or normothermia (group 2: n = 3; 37 degrees C, 3H) after TBI. Six genome arrays were applied to detect the gene expression profiles of ipsilateral hippocampus. Functional clustering and gene ontology analysis were then carried out. Another 20 rats were randomly assigned to 4 groups (n = 5 per group): group 3, sham-normothermia; group 4, sham-hypothermia; group 5, TBI-normothermia; and group 6, TBI-hypothermia. Real-time fluorescent quantitative reverse-transcription polymerase chain reaction was used to detect specific selected genes., Results: We found that 133 transcripts in the hypothermia group were statistically different from those in the normothermia group, including 57 transcripts that were upregulated and 76 that were downregulated after TBI (P < .01). Most of these genes were involved in various pathophysiological processes, and some were critical to cell survival. Analysis showed that 9 gene ontology categories were significantly affected by hypothermia, including the most affected categories: synapse organization and biogenesis (upregulated) and regulation of inflammatory response (downregulated). The mRNA expression of Ank3, Cmbp, Nrxn3, Tgm2, and Fcgr3 was regulated by hypothermia, TBI, or a combination of TBI and hypothermia compared with the sham-normothermia group. Their mRNA expression was significantly regulated by hypothermia in TBI groups., Conclusion: Posttraumatic mild hypothermia has a significant effect on the gene expression profiles of the hippocampus, especially those genes belonging to the 9 gene ontology categories. Differential expression of those genes may be involved in the most fundamental molecular mechanisms of cerebral protection by mild hypothermia after TBI.

The temporal and regional expression profiles of matrix metalloproteinase-9 (MMP-9), after moderate or severe traumatic brain injury (TBI) were measured to investigate the effects of post-traumatic hypothermia (33 degrees C) or hyperthermia (39 degrees C). In the first phase of this study, adult male Sprague-Dawley rats were randomly assigned to groups of moderate TBI (1.8-2.2 atm), severe TBI (2.4-2.7 atm), and sham-injured control. The rats were killed at 4, 6, 12, 24, 48, and 72 h, or 1 week after TBI, for mRNA and protein analysis. In the second phase, rats underwent moderate fluid percussion brain injury, followed immediately by 4 h of post-traumatic normothermia (37 degrees C), hyperthermia (39 degrees C), or hypothermia (32 degrees C). The rats were killed at 12 and 48 h after TBI for mRNA expression analyses, or killed at 24 and 72 h after TBI for protein expression analyses. Brain samples, including the cerebral cortex and hippocampus (both ipsilateral and contralateral hemispheres of each group), were assayed using RT-PCR and Western blot techniques. MMP-9 levels in both the ipsilateral and contralateral hemispheres were significantly increased after TBI compared with those of sham injured animals (p < 0.01). Two expression peaks of MMP-9 were observed in the ipsilateral cortex and hippocampus. An increase in injury severity was associated with an increase in mRNA (12 and 48 h), and protein (24 and 72 h) levels of MMP-9. Post-traumatic hypothermia attenuated the increase in both the mRNA and protein levels of MMP-9, compared with normothermia and hyperthermia (p < 0.01). In contrast, hyperthermia had no significant effect on mRNA (at 12 h) and protein levels (at 24 h) of MMP-9, compared with normothermic values (p > 0.05), but resulted in a significant increase in the levels of MMP-9 mRNA and protein at 24 and 72 h, respectively (p < 0.01). Increases in MMP-9 mRNA and protein after TBI were proportional to injury severity in this model. The effects of post-traumatic hypothermia on the expression of MMP-9 may partially explain the observed effects of post-traumatic temperature on secondary injury after TBI.

Background: The influx of Na and the depolarization mediated by voltage-gated sodium channels (VGSCs) is an early event in traumatic brain injury (TBI) induced cellular abnormalities and is therefore well positioned as an upstream target for pharmacologic modulation of the pathological responses to TBI. Alteration in the expression of the VGSC alpha-subunit has occurred in a variety of neuropathological states including focal cerebral ischemia, spinal injury, and epilepsy., Objective: In this study, changes in Nav1.6 mRNA and protein expression were investigated in rat hippocampus after TBI., Methods: Forty-eight adult male Sprague Dawley rats were randomly assigned to control or TBI groups. TBI was induced with a lateral fluid percussion device. Expression of mRNA and protein for Nav1.6 in the bilateral hippocampus was examined at 2, 12, 24, and 72 hours after injury by real-time quantitative polymerase chain reaction and Western blot. Immunofluorescence was performed to localize the expression of Nav1.6 protein in the hippocampus., Results: Expression of >Nav1.6 mRNA was significantly up-regulated in the bilateral hippocampus at 2 and 12 hours post-TBI. Significant up-regulation of Nav1.6 protein was identified in the ipsilateral hippocampus from 2 to 72 hours post-TBI and in the contralateral hippocampus from 2 to 24 hours post-TBI. Expression of Nav1.6 occurred predominantly in neurons in the hippocampus., Conclusion: Results of the study showed significant up-regulation of mRNA and protein for Nav1.6 in rat hippocampal neurons after TBI.

Abstract In this study we retrospectively analyzed the outcome of bilateral decompressive craniectomy (BDC) for 37 patients with bilateral malignant diffuse brain swelling following severe traumatic brain injury (TBI). Our 37 patients (Glasgow Coma Scale [GCS] score 6 months of follow-up. The mean ICP was 37.7 +/- 6.4 mm Hg, and the mean CPP was 57.6 +/- 7.5 mm Hg before BDC. The ICP significantly decreased to 27.4 +/- 7.2 mm Hg (p < 0.05) after bone removal, and the CPP significantly increased to 63.3 +/- 8.4 mm Hg (p < 0.05). The ICP had a larger decrease, to 11.2 +/- 7.1 mm Hg (p < 0.05), after opening and enlargement of the dura mater (p < 0.05) compared to the levels seen after bone removal, and CPP significantly increased to 77.8 +/- 8.3 mm Hg (p < 0.05). After surgery, the ICP was elevated, but remained lower than the initial ICP (p < 0.05), and was easily controlled by routine medical treatment in the ensuing days, and the CPP remained above the optimal threshold of 70 mm Hg. The mean follow-up time was 9.4 +/- 3.2 months. In total, 20 patients (54.1%) had favorable outcomes, including 12 patients (32.5%; GOS 4) with moderate deficits, and 8 patients (21.6%; GOS 5) showed good recovery and social reintegration. Also, 17 patients (45.9%) had unfavorable outcomes, including 7 patients (18.9%; GOS 1) who died, 4 patients (10.8%; GOS 2) remained in a vegetative state, and 6 patients (16.2%; GOS 3) had severe deficits. The most common complication was hydrocephalus (7 patients, 18.9%). Our data show that BDC offers immediate reductions in intracranial hypertension, and perhaps contributes to satisfactory outcomes in patients with bilateral diffuse brain swelling following severe TBI.

Clinical randomized controlled trials (RCTs) suggest that mild hypothermia may improve the outcome of severe traumatic brain injured patients with intracranial hypertension when cooling is maintained for longer than 48 h. However, the results are not yet conclusive, and more RCTs are required. Mild hypothermia significantly decreases intracranial pressure (ICP) values when refractory intracranial hypertension cannot be controlled by conventional measures in patients with severe traumatic brain injury (TBI). Prolonged mild-to-moderate hypothermia may be associated with high incidence of pneumonia and hypokalemia, which should be prevented.

In this investigation, we evaluated the effect of post-traumatic mild hypothermia on cell death in the hippocampus after fluid percussion traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were randomly divided into three groups (n = 40/group): TBI with hypothermia treatment (32 degrees C), TBI with normothermia (37 degrees C), and sham injury. The TBI model was induced by a fluid percussion TBI device. Mild hypothermia (32 degrees C) was achieved by partial immersion in a water bath (0 degrees C) under general anesthesia for 4h. All rats were killed at 24 or 72h after TBI. The ipsilateral hippocampal CA1 in all rats were analyzed by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL), and 4',6-diamidino-2-phenylindole (DAPI) staining for determining cell death. Caspase-3 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. At 24h, based on TUNEL and DAPI results, the cell death index was 28.80 +/- 2.60% and 32.10 +/- 1.40% in the normothermia TBI group, while reaching only 14.30 +/- 2.70% and 18.40 +/- 2.10% in the hypothermic TBI group (p < 0.01). Based on RT-PCR and Western blotting results, the expression of caspase-3 was 210.20 +/- 5.30% and 170.30 +/- 4.80% in the normothermic TBI group, while reaching only 165.10 +/- 3.70% and 130.60 +/- 4.10% in the hypothermic TBI group (p < 0.05). At 72h, based on TUNEL and DAPI results, the cell death index was 20.80 +/- 2.50% and 25.50 +/- 1.80% in the normothermic TBI group, while reaching only 10.20 +/- 2.60% and 15.50 +/- 2.10% in the hypothermic TBI group (p < 0.01). Based on RT-PCR and Western blotting results, the expression of caspase-3 was 186.20 +/- 6.20% and 142.30 +/- 5.10% in the normothermic TBI group, versus only 152.10 +/- 3.60% and 120.60 +/- 3.90% in the hypothermic TBI group (p < 0.05). Based on our findings, we conclude that post-traumatic hypothermia significantly attenuates cell death within the hippocampus following fluid percussion injury. Taken together with other studies, these observations support the premise that post-traumatic mild hypothermia can provide cerebral protection for patients with TBI.

Traumatic subdural effusion (TSE) is one of the main associated complications of brain trauma. About half of the asymptomatic TSEs ultimately evolve into chronic subdural hematomas (CSDHs), most of which will be inevitably treated by surgical evacuation. With the emergence of subdural hydroma (SDH), rupture of bridge-veins, bleeding of the hydroma wall, hyperfunction of fibrinolysis and increasing protein content in the hydroma are some of the traditionally cited explanations of the pathogenesis of TSE evolving into CSHD. Despite intensive research and subsequent advances in surgical techniques of CSDH, a single treatment with measurable clinical impact on the evolution interruption has yet to be investigated. Compared with peripheral venous blood, inflammatory cytokines were elevated in TSE and CSDH demonstrated by a number of investigators. Neoformation of capillaries, vascular hyper-permeability, serum protein exudation and other characteristics of aseptic inflammatory reaction were observed. Meanwhile, steroid was applied to treat CSDH in several groups, which was generally used as an effective anti-inflammatory agent. Based on systemic thinking, we hypothesize that TSE and CSDH are different stages, with different appearances, of the same inflammatory reaction. The evolution from TSE into CSDH and propagation of CSDH seem to be the results of local aseptic inflammation. Our hypothesis holds potential as a target for therapeutic intervention.

Purpose of Review: The aim of this article is to review the current status of protective effects of mild-to-moderate hypothermia on traumatic brain injury., Recent Findings: More than 30 clinical studies have reported effects of therapeutic hypothermia on outcome of traumatic brain injury and cerebral ischemia. Only one clinical trial of short-term mild hypothermia did not show any effect in patients with severe traumatic brain injury. Long-term mild hypothermia may be useful for severe traumatic brain-injured patients., Summary: Mild-to-moderate hypothermia plays a significant role in cerebral protection after traumatic brain injury.

Background: The occurrence of violent trauma has recently increased, and it has become both a social and medical problem in China. We are the first to explore violent head trauma in China., Methods: Patients with violent head trauma were taken from all hospitalized patients with head trauma from January 2001 to December 2006 admitted to 11 hospitals in China. The rate, causes, age, sex, injury severity (GCS score), CT findings, management, outcome, and complications of patients with violent head trauma were retrospectively analyzed., Results: Two thousand two hundred fifty-four (9.46%) patients with violent head trauma were found among a total of 23816 hospitalized patients with head trauma at 11 hospitals. Violent head trauma was caused by blunt objects (n = 1260, 55.90%), sharp/cutting instruments (n = 271, 12.02%), gunshots (n = 10, 0.44%), and others (n = 713, 31.63%). Violent head trauma was more likely to be found men (n = 1890, 83.85%) and in persons aged 21 to 40 years (n = 1216, 53.95%). In 2254 patients with violent head trauma, scalpel injury was seen in 1277 cases, skull fracture in 786 cases, cerebral contusion in 285 cases, and intracranial hematomas in 898 cases. Five hundred eighty-nine (26.13%) patients had body violent trauma besides violent head trauma. A GCS score of 13 to 15 was found in 1869 (82.92%) patients, 9 to 12 in 166 (7.36%), and 8 or less in 219 (9.72%). One thousand forty-two patients got surgical treatment, and another 1212 received medical management. One thousand nine hundred thirty-one (85.67%) patients had good recovery, 141 (6.47%) had moderate deficits, 36 (1.65%) had severe deficits, 7 (0.32%) had PVS, 63 (2.89%) died, and for the other 76, records were lost., Conclusions: Violent head trauma is certainly both a social and medical problem now, which indicates that violence should be controlled and that the human right of social safety needs to be improved in China.

To compare the effect of long-term mild hypothermia versus short-term mild hypothermia on the outcome of 215 severe traumatic brain injured patients with cerebral contusion and intracranial hypertension. At three medical centers, 215 patients aged 18 to 45 years old with an admission Glasgow Coma Scale < or =8 within 4 h after injury were randomly divided into two groups: long-term mild hypothermia group (n = 108) for 5+/-1.3 days mild hypothermia therapy and short-term mild hypothermia group (n = 107) for 2+/-0.6 days mild hypothermia therapy. All patients had intracranial hypertension and frontotemporoparietal contusion with midline shift >1 cm confirmed on computed tomographic scan. Glasgow Outcome Scale at 6-month follow-up, 47 cases had favorable outcome (43.5%), and other 61 cases had unfavorable outcome (56.5%) in the long-term mild hypothermia group. However, only 31 cases had favorable outcome (29.0%), and other 76 cases had unfavorable outcome (71.0%) in the short-term mild hypothermia group (P < 0.05). The intracranial pressure significantly rebounded after rewarming in the short-term mild hypothermia group, but not in the long-term mild hypothermia (P < 0.05). Furthermore, the incidence of stress ulcer, epilepsy, pulmonary infection, intracranial infection did not significantly differ between the two groups (P > 0.05). Compared with short-term mild hypothermia, long-term mild hypothermia significantly improves the outcome of severe traumatic brain injured patients with cerebral contusion and intracranial hypertension without significant complications. Our data suggest that 5 days of long-term cooling is more efficacious than 2 days of short-term cooling when mild hypothermia is used to control refractory intracranial hypertension in patients with severe traumatic brain injury.

To compare the effect of standard trauma craniectomy (STC) versus limited craniectomy (LC) on the outcome of severe traumatic brain injury (TBI) with refractory intracranial hypertension, we conducted a study at five medical centers of 486 patients with severe TBI (Glasgow Coma Scale score 0.05). The results of the study indicate that STC significantly improves outcome in severe TBI with refractory intracranial hypertension resulting from unilateral frontotemporoparietal contusion with or without intracerebral or subdural hematoma. This suggests that STC, rather than LC, be recommended for such patients.

Objective: To determine the effect of arousal methods for prolonged coma of 175 patients with severe traumatic brain injury and related factors., Methods: There were 175 cases with persistent coma longer than 1 month after severe traumatic brain injury. Coma lasted 1-12 months. Arousal procedures included hyperbaric oxygen, physical therapy and arousal drugs., Results: In the 175 prolonged coma patients 110 got recovery of consciousness; in 118 cases with coma of 1-3 months, 86 cases recovered consciousness (72.9%); in 42 cases with coma of 4-6 months, 20 cases recovered consciousness (47.6); and in 15 cases with coma of longer than 6 months, only 4 cases recovered consciousness (26.7%). The recovery of consciousness depended on patient's primary brain stem damage, cerebral hernia, GCS score, and age., Conclusions: Application of appropriate arousal procedures improves recovery of consciousness in patients with prolonged coma.

Objective: To study the effect of standard large trauma craniotomy (SLTC) on outcomes of patients with severe traumatic brain injury (TBI) (GCS<=8)., Methods: 230 patients with severe TBI were randomly divided into two groups. 115 patients underwent SLTC (10 cm x 12 cm) as an SLTC group, and other 115 patients underwent temporo-parietal or fronto-temporal craniotomy (6 cm x 8 cm) according to the position of hematomas as a routine craniotomy (RC) group. Other treatments were identical in two groups. According to Glasgow outcome scale (GOS), the prognosis of the patients was evaluated and the complications were compared between two groups., Results: 27 patients got good outcome and moderate disability (23.5%), 40 severe disability and vegetative survival (34.8%), and 48 died (41.7%) in SLTC group. 21 patients got good outcome and moderate disability (18.3%), 28 severe disability and vegetative survival (24.3%), and 66 died (57.4%) in RC group. The incidence of incision hernia was lower in SLTC group than in RC group. However, the incidence of operative encephalocele, traumatic epilepsy and intracranial infection were not different in two groups., Conclusions: Standard large trauma craniotomy significantly reduces the mortality of patients with severe TBI without serious complications, but does not improve the life quality of the patients.

Objective: To observe the effects of ganglioside GM1 on reduction of brain edema and amelioration of cerebral metabolism after traumatic brain injury (TBI)., Methods: An acute experimental closed TBI model in rats was induced by a fluid-percussion brain injury model. At five and sixty minutes after TBI, the animals were intraperitoneally injected by ganglioside GM1 (30 mg/kg) or the same volume of saline. At the 6th hour after TBI, effects of ganglioside GM1 or saline on changes of mean arterial pressure (MAP), contents of water, lactic acid (LA) and lipid peroxidation (LPO) in the injured cerebral tissues were observed., Results: After TBI, MAP decreased and contents of water, LA and LPO increased in brain injury group; however, MAP was back to normal levels and contents of water, LA and LPO decreased in ganglioside GM1 treated group, compared with those in brain injury group (P < 0.05). No significant difference between the saline treated group and the brain injury group (P > 0.05) was observed., Conclusions: Ganglioside GM1 does have obvious neuroprotective effect on early TBI.

A number of factors, including Glasgow coma scale (GCS) score, age, pupillary response and size, hypoxia, hyperthermia, and high intracranial pressure, may play an important role in predicting the outcome of traumatic brain injury. Eight hundred forty-six cases of severe traumatic brain injury (GCS < or = 8) were analyzed retrospectively to clarify the effects of multiple factors on the prognosis of patients. At 1 year after injury, the outcomes in these cases were as follows: good recovery, 31.56%; moderate disability, 14.07%; severe disability 24.35%; vegetative status, 0.59%; and death, 29.43%. The outcomes were strongly correlated (p < 0.05) with GCS score, age, pupillary response and size, hypoxia, hyperthermia, and high intracranial pressure (ICP). These findings indicate that prevention of hypoxia, control of high ICP, and prevention of hyperthermia may be useful means for improving the outcome of patients with severe head injury.

We have used an animal model of traumatic brain injury (TBI) that incorporates both the neurotransmitter toxicity of fluid percussion TBI and deafferentation of bilateral entorhinal cortical (BEC) lesion to explore whether administration of muscarinic cholinergic or N-methyl-D-aspartate glutamatergic antagonists prior to injury ameliorates cognitive morbidity. Fifteen minutes prior to moderate central fluid percussion TBI, rats were given intraperitoneal injections of either scopolamine (1.0 mg/kg) or MK-801 (0.3 mg/kg) and 24 hr later underwent BEC lesion. Body weight was followed for 5 days postinjury, as was beam balance and beam walk performance to assure motor recovery prior to spatial memory testing. Each group was assessed for spatial memory deficits with the Morris water maze at short term (days 11-15) and long-term (60-64 days) postinjury intervals and then compared with untreated combined insult and sham-injured controls. Results showed that each drug significantly elevated body weight relative to untreated injured cases. Both scopolamine and MK-801 reduced beam balance deficits, whereas neither drug had a significant effect on beam walk deficits. Interestingly, short-term cognitive deficits assessed on days 11-15 were differentially affected by the two drugs: MK-801 pretreatment enhanced the recovery of spatial memory performance, whereas scopolamine pretreatment did not. Long-term (days 60-64) deficits in spatial memory were not altered by pretreatment with either drug. Our results suggest that, unlike fluid percussion TBI alone, behavioral impairment may require more select intervention when deafferentation is part of the head trauma pathology.

We have identified alterations in the responses of muscarinic and metabotropic receptors in rat hippocampus that persist for at least 15 days after central fluid percussion injury. This study compares the effect of lateral fluid percussion and central fluid percussion on these responses. Moderate injury was obtained by displacement and deformation of the brain within the closed cranial cavity using a fluid percussion device positioned either centrally or laterally. Carbachol and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated polyphosphoinositide (PPI) hydrolysis was assayed in hippocampus from injured and sham-injured controls at 15 days following injury. At 15 days after central fluid percussion traumatic brain injury (TBI), the response to carbachol was enhanced by 30% and the response to trans-ACPD was enhanced by 75% compared to sham-injured animals. At 15 days after lateral fluid percussion TBI the response to trans-ACPD was enhanced by 40% both ipsilateral and contralateral to the side of injury. In contrast, the response to carbachol was enhanced by 29% contralateral to the side of injury but was diminished by 12% ipsilateral to the side of injury. Cresyl violet staining shows no hippocampal cell death after central fluid percussion injury or on the side contralateral to lateral fluid percussion injury but on the ipsilateral side cell death was identified in hippocampal area CA3. Thus, abnormal hippocampal cell signaling through the phosphoinositide pathway occurs in the absence of cell death and may contribute to cognitive impairment.

We examined the effects of an exogenous mu opioid agonist and antagonist on systemic physiology and neurological outcome following TBI in the rat. Experiment I: [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) (0.1 nMol or 0.3 nMol in 5 microliters) (n = 10) or artificial CSF (n = 10) was administered 5 min prior to fluid-percussion brain injury (2.1 atmospheres). Motor performance was assessed on days 1-5 after TBI. The mu receptor agonist, DAMGO significantly reduced both beam-walking latency and body weight loss after injury (p < 0.05). DAMGO-treated rats (n = 5) did not differ from CSF-treated rats (n = 5) on either systemic arterial blood pressure or heart rate responses to injury. Experiment II: Beta-funaltrexamine (beta-FNA) (20.0 nMol in 5.0 microliters) (n = 10) or artificial CSF (n = 10) was administered (icv) to rats 5 min prior to fluid-percussion brain injury (1.8 atmospheres). Motor performance was assessed on days 1-5 after TBI. The mu receptor antagonist, beta-FNA, significantly increased beam-walking latency after injury (p < 0.05). beta-FNA-treated rats (n = 5) did not differ from CSF-treated rats (n = 5) on either systemic arterial blood pressure or heart rate responses to injury. Experiment III: Neither beta-FNA nor DAMGO affected motor performance in uninjured rats. These results suggest that activation of mu opioid receptors by exogenous agonists may provide protection against deficits in motor performance produced by fluid percussion brain injury.

In the fluid percussion model of traumatic brain injury (TBI), we examined muscarinic and metabotropic glutamate receptor-stimulated polyphosphoinositide (PPI) turnover in rat hippocampus. Moderate injury was obtained by displacement and deformation of the brain within the closed cranial cavity using a fluid percussion device. Carbachol and (+/-)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated PPI hydrolysis was assayed in hippocampus from injured and sham-injured controls at both 1 hour and 15 days following injury. At 1 hour after TBI, the response to carbachol was enhanced in injured rats by up to 200% but the response to trans-ACPD was diminished by as much as 28%. By contrast, at 15 days after TBI, the response to carbachol was enhanced by 25% and the response to trans-ACPD was enhanced by 73%. The ionotropic glutamate agonists N-methyl-D-aspartate (NMDA), and alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionate (AMPA), did not increase PPI hydrolysis in either sham or injured rats and injury did not alter basal hydrolysis. Thus, hippocampal muscarinic and metabotropic receptors linked to phospholipase C are differentially altered by TBI.

Laboratory studies indicate that activation of muscarinic cholinergic receptors (mAChRs) at or soon after traumatic brain injury (TBI) significantly contributes to behavioral morbidity. Recent research has demonstrated that pre-injury treatment with the muscarinic antagonist scopolamine significantly reduces spatial memory deficits at 11-15 days post-TBI. In the present study, we examined mAChR binding kinetics in brain regions at 15 days after moderate (1.95 atm) fluid percussion TBI in untreated and scopolamine-treated rats. Three groups were examined: untreated TBI (n = 8), TBI with pre-injury scopolamine treatment (1.0 mg/kg, i.p., 15 min prior to injury) (n = 11), and sham-injury (n = 7). The affinity (Kd) and maximum number of binding sites (Bmax) of mAChRs in hippocampus, neocortex, and brainstem were determined by [3H]QNB binding. Bmax values in TBI animals were significantly higher in hippocampus (4061 +/- 494 fmol/mg protein) and neocortex (4272 +/- 640 fmol/mg protein), but not in brainstem (833 +/- 39 fmol/mg protein) compared to sham-injured controls (hipp. 2812 +/- 218 fmol/mg/protein; neoctx. 2850 +/- 129 fmol/mg protein; brainstem 794 +/- 26 fmol/mg protein) (P < 0.05). At 15 days after injury, Bmax values of mAChRs in TBI animals with pre-injury scopolamine treatment (hipp. 2850 +/- 129 fmol/mg protein; neoctx. 2948 +/- 123 fmol/mg protein) did not differ from control. In all brain regions, Kd values did not differ between groups. These results demonstrate that TBI significantly alters the binding sites of mAChRs in hippocampus and neocortex for as long as 15 days after TBI. Furthermore, these results indicate that a pharmacological treatment that improves motor and memory function outcome also normalizes aspects of mAChRs physiology. These data suggest that excessive activation of mAChRs at or soon after TBI impact contributes to long-term pathophysiological processes in TBI.

Recent evidence suggests that excessive activation of muscarinic cholinergic receptors (mAChRs) contributes significantly to the pathophysiological consequences of traumatic brain injury (TBI). To examine possible alterations in mAChRs after TBI, the affinity (Kd) and maximum number of binding sites (Bmax) of mAChRs in hippocampus, neocortex, brain stem and cerebellum were determined by [3H]QNB binding. Three groups of rats were examined: 1 h post-TBI (n = 21), 24 h post-TBI (n = 21) and sham-injured rats (n = 21). Kd values were significantly higher in hippocampus and brain stem at 1 but not 24 h post-TBI compared with sham-injured controls (P < 0.05). Kd values did not significantly differ in neocortex and cerebellum at 1 or 24 h post-TBI compared with sham-injured controls. Bmax values did not significantly differ in any brain areas at 1 or 24 h post-TBI compared with sham-injured controls. These results show that TBI significantly decreases the affinity of mAChRs in hippocampus and brain stem at an early stage post-TBI, which may contribute to desensitization of mAChRs after TBI. The findings of no change in Bmax values are consistent with a transient elevation in ACh concentrations after TBI.

Activation of muscarinic acetylcholine (ACh) receptors contributes to the pathophysiological consequences of moderate experimental traumatic brain injury (TBI). Hypothermia (30 degrees C) provides protection in experimental TBI. We measured ACh levels in CSF and plasma 5 min after moderate fluid percussion TBI under normothermic or hypothermic conditions, because ACh in the CSF has been correlated with the severity of behavioral deficits after TBI. Three groups were examined: TBI with hypothermic brain (30 degrees C), TBI with normothermic brain (37 degrees C), or sham TBI with normothermic brain (37 degrees C). ACh concentrations in CSF were significantly higher in 37 degrees C TBI rats, but not in 30 degrees C TBI rats compared to shams. ACh concentrations in plasma did not differ between groups. These results suggest that a contributing factor to the neuroprotective effects of moderate hypothermia in TBI may be related to the reduction of excessive ACh levels in the central nervous system following injury.

The effects of postinjury hypothermia on behavioral outcome following moderate fluid percussion traumatic brain injury (TBI) were examined. In Experiment I, three groups of rats were examined. The first group was normothermic (37.5 degrees C); and hypothermia (30 degrees C) was initiated 15 min and 30 min postinjury in the second and third groups, respectively. Whole body cooling was achieved by ventral ice pack. Cooling of the brain to 30 degrees C was achieved in 25 min and maintained for 60 min. Brain temperature was measured indirectly by a probe in the temporalis muscle. Behavioral outcome was assessed by beam-balance performance, beam-walking performance, and body weight loss measured daily for 5 days after TBI. Both the normothermic group and the 30-min postinjury hypothermic group exhibited significant (p < 0.05) beam-balance and beam-walking deficits on days 1 through 5 after TBI. In contrast, the 15-min postinjury hypothermic group exhibited significant (p < 0.05) beam-walking deficits only on day 1 after TBI and significant (p < 0.05) beam-balance deficits on days 1, 3, and 4 after TBI. In Experiment II, subcortical brain temperature was compared to temporalis muscle temperature in normothermic (37.5 degrees C) and hypothermic (30 degrees C) rats subjected to TBI. In both groups brain temperature tracked within 0.4 degree C of temporalis muscle temperature. These results are similar to post-TBI excitatory receptor antagonist studies and indicate a therapeutic window for moderate hypothermia of less than 30 min after moderate fluid percussion TBI in the rat.

The effects of moderate hypothermia on blood-brain barrier (BBB) permeability and the acute hypertensive response after moderate traumatic brain injury (TBI) in rats were examined. TBI produced increased vascular permeability to endogenous serum albumin (IgG) in normothermic rats (37.5 degrees C) throughout the dorsal cortical gray and white matter as well as in the underlying hippocampi as visualized by immunocytochemical techniques. Vascular permeability was greatly reduced in hypothermic rats cooled to 30 degrees C (brain temperature) prior to injury. In hypothermic rats, albumin immunoreactivity was confined to the gray-white interface between cortex and hippocampi with no involvement of the overlying cortices and greatly reduced involvement of the underlying hippocampi. The acute hypertensive response in normothermic rats peaked at 10 s after TBI (187.3 mm Hg) and returned to baseline within 50 s. In contrast, the peak acute hypertensive response was significantly (P < 0.05) reduced in hypothermic rats (154.8 mm Hg, 10 s after TBI) and returned to baseline at 30 s after injury. These results demonstrate that moderate hypothermia greatly reduces endogenous vascular protein-tracer passage into and perhaps through the brain. This reduction may, in part, be related to hypothermia-induced modulation of the systemic blood pressure response to TBI.

Recent work has shown that mild to moderate levels of hypothermia may profoundly reduce the histological and biochemical sequelae of cerebral ischemic injury. In the present study, the authors examined the effect of fluid-percussion injury on brain temperature in anesthetized rats and the effect of anesthesia on brain temperature in uninjured rats. The relationship between the brain, rectal, and temporalis muscle temperatures during normothermia, hypothermia, and hyperthermia was studied following a moderate magnitude of fluid-percussion brain injury (2.10 to 2.25 atmospheres) in rats. The results showed that mean brain temperature in 10 anesthetized injured rats, in 21 anesthetized uninjured rats, and in 10 unanesthetized uninjured rats was a mean (+/- standard error of the mean) of 36.04 degrees +/- 0.20 degrees C, 36.30 degrees +/- 0.08 degrees C, and 37.95 degrees +/- 0.09 degrees C, respectively. There was no significant difference in temperature under general anesthesia between injured and uninjured rats (p greater than 0.05). In the absence of brain injury, mean brain temperature was significantly lower in anesthetized rats than in unanesthetized rats (p less than 0.001). In anesthetized brain-injured rats, temporalis muscle temperature correlated well with brain temperature over a 30 degrees to 40 degrees C range, even when brain temperature was rapidly changed during induction of hypothermia or hyperthermia (r = 0.9986, p less than 0.0001). In contrast, rectal temperature varied inconsistently from brain temperature. These observations indicated that: 1) brain injury itself does not influence brain temperature in this model; 2) anesthesia alone decreases brain temperature to levels producing cerebral protection in this model; and 3) external monitoring of temporalis muscle temperature can provide a reliable indirect measure of brain temperature in the course of experimental brain injury. The authors believe that it is essential to monitor or control brain temperature in studies of experimental brain injury.

These experiments examined the effects of moderate hypothermia on mortality and neurological deficits observed after experimental traumatic brain injury (TBI) in the rat. Brain temperature was measured continuously in all experiments by intraparenchymal probes. Brain cooling was induced by partial immersion (skin protected by a plastic barrier) in a water bath (0 degrees C) under general anesthesia (1.5% halothane/70% nitrous oxide/30% oxygen). In experiment I, we examined the effects of moderate hypothermia induced prior to injury on mortality following fluid percussion TBI. Rats were cooled to 36 degrees C (n = 16), 33 degrees C (n = 17), or 30 degrees C (n = 11) prior to injury and maintained at their target temperature for 1 h after injury. There was a significant (p less than 0.04) reduction in mortality by a brain temperature of 30 degrees C. The mortality rate at 36 degrees C was 37.5%, at 33 degrees C was 41%, and at 30 degrees C was 9.1%. In experiment II, we examined the effects of moderate hypothermia or hyperthermia initiated after TBI on long-term behavioral deficits. Rats were cooled to 36 degrees C (n = 10), 33 degrees C (n = 10), or 30 degrees C (n = 10) or warmed to 38 degrees C (n = 10) or 40 degrees C (n = 12) starting at 5 min after injury and maintained at their target temperatures for 1 h. Hypothermia-treated rats had significantly less beam-walking, beam-balance, and body weight loss deficits compared to normothermic (38 degrees C) rats. The greatest protection was observed in the 30 degrees C hypothermia group.(ABSTRACT TRUNCATED AT 250 WORDS)

beta-endorphin-like immunoreactivity (beta-ELI) was measured in the cerebrospinal fluid (CSF) of 36 patients with acute head injury and 12 controls. The mean values of beta-ELI in CSF of controls and patients with moderate and severe acute head injury were 51.9 +/- 5.6 pg/ml, 110.5 pg/ml, and 173.8 +/- 20.1 pg/ml respectively, with significant difference between them (p less than 0.05). The results showed that beta-ELI increased in CSF of acute head injury patients.