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PubMed1997

Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury.

Traumatic brain injury (TBI) is associated with primary and secondary injury. A thorough understanding of secondary injury will help to develop effective treatments and improve patient outcome. In this study, the GM model of controlled cortical impact injury (CCII) of Lighthall (1988) was used with modification to induce lateral TBI in rats. Forebrain mitochondria isolated from ipsilateral (IH) and contralateral (CH) hemispheres to impact showed a distinct difference. With glutamate + malate as substrates, mitochondria from the IH showed a significant decrease in State 3 respiratory rates, respiratory control indices (RCI), and P/O ratios. This decrease occurred as early as 1 h and persisted for at least 14 days following TBI. The State 3 respiratory rates, RCI, and P/O ratios could be restored to sham values by the addition of EGTA to the assay mixture. A significant amount of Ca2+ was found to be adsorbed to the mitochondria of both the IH and the CH with higher values seen in the IH. The rate of energy-linked Ca2+ transport in the IH was significantly decreased at 6 and 12 h. These data indicate that CCII-induced TBI perturbs cellular Ca2+ homeostasis and results in excessive Ca2+ adsorption to the mitochondrial membrane, which subsequently inhibits the respiratory chain-linked electron transfer and energy transduction.

Animals↗
PubMed2000

Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury.

Traumatic brain injury (TBI) results in the rapid necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage resulting in significant neurological dysfunction. Recent reports from our lab demonstrate that a bolus injection of the immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. CsA transiently inhibits the opening of the mitochondrial permeability transition pore and maintains calcium homeostasis in isolated mitochondria. The present study utilized a unilateral controlled cortical impact model of TBI to assess whether the neuroprotective effects of CsA could be extended by chronic infusion. Adult rats were subjected to a moderate (2 mm) cortical deformation and the extent of cortical damage was assessed using modern stereological techniques. Animals were administrated a 20 mg/kg intraperitoneal bolus of CsA or vehicle 15 min postinjury and osmotic minipumps were implanted subcutaneously to deliver CsA (4.5 or 10 mg/kg/day) or vehicle. All animals receiving CsA demonstrated a significant reduction in lesion volume, with the highest dose offering the most neuroprotection (74% reduction in lesion volume). These results extend our previous findings and demonstrate that chronic infusion of CsA is neuroprotective following TBI. These findings also suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation.

Animals↗
PubMed2003

Magnetization transfer and T2 quantitation in normal appearing cortical gray matter and white matter adjacent to focal abnormality in patients with traumatic brain injury.

Traumatic brain injury (TBI) is one of the commonest causes of morbidity and mortality in the developed countries with posttraumatic epilepsy and functional disability being its major sequelae. The purpose of this study was to test the hypothesis whether the normal appearing adjacent gray and white matter regions on T2 and T1 weighted magnetization transfer (MT) weighted images show any abnormality on quantitative imaging in patients with TBI. A total of 51 patients with TBI and 10 normal subjects were included in this study. There were significant differences in T2 and MT ratio values of T2 weighted and T1 weighted MT normal appearing gray matter regions adjacent to focal image abnormality compared to normal gray matter regions in the normal individuals as corresponding contralateral regions of the TBI patient's group (p < 0.05). However the adjoining normal appearing white matter quantitative values did not show any significant change compared to the corresponding contralateral normal white matter values. We conclude that quantitative T2 and MT ratio values provide additional abnormality in patients with TBI that is not discernable on conventional T2 weighted and T1 weighted MT imaging especially in gray matter. This additional information may be of value in overall management of these patients with TBI.

Adolescent↗
PubMedDate not supplied

Event-related potential in facial affect recognition: potential clinical utility in patients with traumatic brain injury.

Traumatic brain injury (TBI) frequently leads to deficits in social behavior. Prior research suggests that such deficits may result from impaired perception of basic social cues. However, these social-emotional deficits have not been studied electrophysiologically. We measured the P300 event-related potential (ERP), which has been shown to be a sensitive index of cognitive efficiency, in 13 patients with a history of moderate to severe TBI and in 13 healthy controls. The P300 response was measured during detection of 30 pictures of angry faces (rare target) randomly distributed among 120 neutral faces (frequent nontarget). Compared to control subjects, the TBI group's P300 responses were significantly delayed in latency (p = 0.002) and lower in amplitude (p = 0.003). TBI patients also showed slower reaction times and reduced accuracy when manually signaling their detection of angry faces. Coefficients of variation (CV) for the facial P300 response compared favorably to those of many standard clinical assays, suggesting potential clinical utility. For this study, we demonstrated the feasibility of studying TBI patients' P300 responses during the recognition of facial affect. Compared to controls, TBI patients showed significantly impaired electrophysiological and behavioral responses while attempting to detect affective facial cues. Additional studies are required for clinicians to determine whether this measure is related to patients' psychosocial function in the community.

Affect↗
PubMed2005

Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury.

Traumatic brain injury (TBI) is a common cause of cognitive dysfunction and a major risk factor for Alzheimer's disease (AD). PDAPP mice, a transgenic line overexpressing a mutant human amyloid precursor protein (APP) implicated in familial AD, have markedly impaired behavioral performance in the Morris water maze relative to wild-type (WT) littermates. Performance further deteriorates following experimental TBI in both PDAPP and WT mice. However, the aspects of cognitive function involved are not well understood. Here, we have analyzed search strategies used in the water maze by 3-4 month old PDAPP and WT C57Bl6 littermates both before and after moderate controlled cortical impact TBI. Prior to TBI, PDAPP mice used less spatial strategies and more nonspatial systematic strategies and strategies involving repetitive looping than WT mice. With training, PDAPP mice used more spatial strategies and less repetitive looping. After TBI, PDAPP mice lost use of spatial strategies and relied more on repetitive looping. TBI in WT mice also reduced their use of spatial strategies but instead caused a switch to nonspatial systematic strategies. We also analyzed changes in the efficiency with which mice used each individual strategy, but found that differences in which strategies were used quantitatively accounted for most of the differences in performance between groups. These results demonstrate that suboptimal search strategy use in addition to effects on spatial learning and memory underlies the impaired performance of PDAPP mice and further deterioration following TBI. Human TBI patients may have analogous poor use of problem solving strategies.

Amyloid beta-Protein Precursor↗
PubMed2026

Artificial Intelligence-Driven Multi-Omics Analysis Reveals Hydroxytyrosol Targeting of the TXNIP-NLRP3 Inflammasome Axis in Traumatic Brain Injury.

Traumatic brain injury (TBI) induces secondary neuroinflammation driven by oxidative stress, inflammasome activation, and immune remodeling, yet specific mechanism-guided pharmacological interventions remain limited. This study established an artificial intelligence (AI)-integrated network pharmacology and multi-omics framework to evaluate whether hydroxytyrosol (HT), an olive-derived natural polyphenol, may regulate TBI-related neuroinflammatory targets centered on the TXNIP/NLRP3 inflammasome axis. Starting from the SMILES structure of HT, potential targets were predicted using PharmMapper, SwissTargetPrediction, and the Similarity Ensemble Approach and were standardized to UniProt identifiers. TBI-associated genes were integrated from GeneCards, DisGeNET, OMIM, and the Therapeutic Target Database. The overlapping target set was analyzed using STRING-based protein-protein interaction (PPI) networks, MCODE, CytoHubba, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Public GEO transcriptomic datasets (GSE123831 and GSE104687) were used for cross-platform expression validation, differential expression analysis, and exploratory CIBERSORT-based immune infiltration estimation. Random forest (RF), multilayer perceptron (MLP), graph convolutional network (GCN), graph attention network (GAT), SHAP/LIME explainability analysis, LASSO inflammatory-risk scoring, and two-sample Mendelian randomization (MR) were further applied for target prioritization, immune phenotype mapping, and genetic association analysis. Seventy-three overlapping HT-TBI targets were identified. PPI and topology analyses prioritized TXNIP, NLRP3, CASP1, MAPK1, and TP53 as key hubs enriched in inflammasome activation, oxidative stress, apoptosis, and NOD-like receptor signaling. TXNIP, NLRP3, and CASP1 were consistently upregulated in both TBI transcriptomic datasets. LM22-based immune deconvolution suggested increased pro-inflammatory immune signatures and a positive TXNIP-M1 macrophage association (r&#x202f;=&#x202f;0.63, p < 0.001), which should be interpreted as a transcriptome-derived hypothesis rather than validated murine immune-cell proportions. AI-based models consistently ranked TXNIP/NLRP3 as high-contribution features under internal validation, and removal of these targets reduced model performance. A five-gene inflammatory score achieved an internally evaluated AUC of 0.87, while two-sample MR supported positive genetic associations involving TXNIP expression, TBI risk, NLRP3 and IL-1&#x3b2; expression. Collectively, these findings prioritize the TXNIP/NLRP3/CASP1 module as a computationally supported candidate mechanism through which HT may influence oxidative stress-inflammasome-immune coupling in TBI. This study provides an interpretable drug-target-pathway-phenotype framework and identifies TXNIP, NLRP3, and CASP1 as priority nodes for future experimental validation.

Artificial Intelligence↗
PubMed2001

[Study on maxillofacial impact injury associated with brain injury].

OBJECTIVE: The purpose was to study the mechanism and the characteristics of brain damage associated with maxillofacial injury under the impacting load of middle face. METHODS: Eighteen rabbits were subjected to impacting on left middle face with pneumatic impact device, which were horizontally located on the ground. The impact velocities respectively were 4.77 m/s +/- 0.53 m/s (group A), 9.16 m/s +/- 0.65 m/s (group B) and 13.95 m/s +/- 0.67 m/s (group C). The acceleration of head and stress of encephalic was monitored during the impact period. The pathological characteristics of correlative tissues were examined in detail 6 hours after impacting. The contents of LPO, SOD and NO in blood and water in brain were measured at the same time. RESULTS: The contents of LPO and SOD in blood significantly increased along with the increasing of impact velocity (P < 0.05). The same pattern was observed in the changing of water content of brain (P < 0.05). But the contents of NO in blood reduced when the impact velocity increased (P < 0.05). The animals of group A showed single fracture of middle face bone, while Group B showed multiple fractures of middle face bone. Group C represented severe maxillofacial injury associated with brain damage. The pathological damage of brain became more serious along with the increase of impact velocity. The peak value of head acceleration and encephalic stress of group C were higher than that of group A and group B (P < 0.05). CONCLUSION: The responses of head acceleration and encephalic stress resulting from middle face impacting might play a key role in brain injury associated with maxillofacial injury.

Animals↗
PubMed2001

Reduced hippocampal volume in association with p50 nonsuppression following traumatic brain injury.

Traumatic brain injury (TBI) may produce persistently impaired auditory gating. This cholinergic-dependent, hippocampally mediated preattentive cognitive function that facilitates filtering of auditory stimuli may be indexed by the P50 evoked waveform to paired auditory stimuli. Abnormal P50 suppression post TBI is believed to result from injury to the hippocampus and/or its afferent cholinergic projections. This hypothesis was tested by comparing hippocampal and total brain volumes on MRI between ten P50-nonsuppressing TBI patients and ten normal control subjects matched for age, gender, and education. TBI subjects had highly significant bilateral hippocampal volume reductions, even when covaried for reductions in total brain volume. Degree of volume loss was not correlated with initial TBI severity. Findings support the hypothesis that hippocampal injury underlies P50 nonsuppression post TBI and suggest that such structural abnormalities may be observed even in "mildly" injured persons.

Adult↗
PubMed1993

Hypothermia attenuates the loss of hippocampal microtubule-associated protein 2 (MAP2) following traumatic brain injury.

Traumatic brain injury (TBI) produces a tissue-specific decrease in protein levels of microtubule-associated protein 2 (MAP2), an important cross-linking component of the neuronal cytoskeleton. Because moderate brain hypothermia (30 degrees C) reduces certain neurobehavioral deficits produced by TBI, we examined the efficacy of moderate hypothermia (30 degrees C) in reversing the TBI-induced loss of MAP2 protein. Naive, sham-injured, and moderate (2.1 atm) fluid percussion-injured rats were assessed for MAP2 protein content 3 h post injury using quantitative immunoreactivity measurements. Parallel groups of sham-injured and fluid percussion-injured animals were maintained in moderate hypothermia (30 degrees C), as measured by temporalis muscle temperature, for MAP2 quantitation 3 h post injury. No difference in MAP2 levels was observed between naive and sham-injured normothermic animals. Hypothermia alone had no effect on soluble MAP2 levels in sham-injured animals compared with normothermic sham-injured controls (88.0 +/- 7.3%; p > 0.10). Fluid percussion injury dramatically reduced MAP2 levels in the normothermic group (44.3 +/- 5.9%; p < 0.0005) compared with normothermic sham-injured controls. No significant reduction of MAP2 was seen in the hypothermic injured group (95.2 +/- 4.6%; compared with hypothermic sham-injured controls, p > 0.20). Although it is premature to infer any causal link, the data suggest that the attenuation of injury-induced MAP2 loss by hypothermia may contribute to its overall neuroprotective action.

Animals↗
PubMed1994

The hemispheric cerebrovascular response to hemodilution is attenuated by a focal cryogenic brain injury.

Experimental brain injury attenuates the normal increase in cerebral blood flow (CBF) that accompanies a fall in PaO2, and this may contribute to the well-known detrimental effects of hypoxia following closed head injury. Anemia is also known to adversely affect posttraumatic survival, and it is reasonable to hypothesize that this too may be related to an altered cerebrovascular response. Therefore, to examine this possibility, pentobarbital-anesthetized rabbits were subjected to a left posterior parietal cryogenic cortical injury, followed 90 min later by isovolemic hemodilution with hetastarch. Unlesioned control animals underwent an identical degree of hemodilution. CBF was measured using radioactive microspheres. In control animals, hemodilution was accompanied by a marked increase in CBF in all brain regions. For example, in the left posterior cortex, CBF increased from 30 +/- 14 mL/100 g/min (baseline Hct = 42 +/- 2%, mean +/- SD) to 100 +/- 20 mL/100 g/min at Hct = 12 +/- 1%. By contrast, there was a markedly attenuated response throughout the left (ipsilateral) hemisphere of injured animals, even in cortical regions distant from the injury. For example, in the left posterior cortex, CBF changed from a baseline of 32 +/- 21 mL/100 g/min (baseline) to 40 +/- 14 mL/100 g/min at the lowest Hct. CBF responses to hemodilution were unaltered in the contralateral hemisphere and in the hindbrain. These data indicate that a localized brain lesion can produce widespread ipsilateral alterations in the CBF response to hemodilution, with resultant compromise in cerebral O2 delivery. These data support the argument that the CBF increase produced by hemodilution is an active vasodilatory process rather than a passive response to changing blood viscosity.

Animals↗
PubMed2006

Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury.

Traumatic brain injury (TBI) often produces cognitive impairments by primary or secondary neuronal loss. Stem cells are a potential tool to treat TBI. However, most previous studies using rodent stem or progenitor cells failed to correlate cell grafting and cognitive improvement. Furthermore, the efficacy of fetal human neural stem cells (hNSCs) for ameliorating TBI cognitive dysfunction is undetermined. This study therefore characterized phenotypic differentiation, neurotrophic factor expression and release and functional outcome of grafting hNSCs into TBI rat brains. Adult Sprague-Dawley rats underwent a moderate parasagittal fluid percussion TBI followed by ipsilateral hippocampal transplantation of hNSCs or vehicle 1 day post-injury. Prior to grafting, hNSCs were treated in vitro for 7 days with our previously developed priming procedure. Significant spatial learning and memory improvements were detected by the Morris water maze (MWM) test in rats 10 days after receiving hNSC grafts. Morphological analyses revealed that hNSCs survived and differentiated mainly into neurons in the injured hippocampus at 2 weeks after grafting. Furthermore, hNSCs expressed and released glial-cell-line-derived neurotrophic factor (GDNF) in vitro and when grafted in vivo, as detected by RT-PCR, immunostaining, microdialysis and ELISA. This is the first direct demonstration of the release of a neurotrophic factor in conjunction with stem cell grafting. In conclusion, human fetal neural stem cell grafts improved cognitive function of rats with acute TBI. Grafted cells survived and differentiated into neurons and expressed and released GNDF in vivo, which may help protect host cells from secondary damage and aid host regeneration.

Animals↗
PubMed1997

Hypoxic-ischemic brain injury in the newborn. Cellular mechanisms and potential strategies for neuroprotection.

Recent advances have delineated many of the complex cellular mechanisms of cerebral hypoxic-ischemic injury. These developments have created opportunities for the design of rational "mechanism-based" strategies that target specific injurious processes. A number of neuroprotective agents have entered adult clinical trial and practice. For the newborn infant, progress in this areas has been judiciously delayed by toxicity concerns. Central to those safety concerns is the close relationship between mechanisms of hypoxic-ischemic cellular injury and normal developmental processes. These cellular mechanisms and the dilemmas facing the advance of this field are discussed. The likelihood of an effective single "magic bullet" neuroprotective strategy emerging in the near future appears remote. Rather more likely is the development of "cocktail" therapies that seek to exploit synergistic antagonism at multiple levels in the complex concentration of cellular events mediating hypoxic-ischemic cellular injury. However, such combination therapies will require elucidation of the complex inter-relationships between mechanisms of cellular injury, brain development, and the combination of therapies envisioned.

Brain↗
PubMed2006

Energy metabolic changes in the early post-injury period following traumatic brain injury in rats.

Impaired cerebral energy metabolism may be a major contributor to the secondary injury cascade that occurs following traumatic brain injury (TBI). To estimate the cortical energy metabolic state following mild and severe controlled cortical contusion (CCC) TBI in rats, ipsi-and contralateral cortical tissues were frozen in situ at 15 and 40 min post-injury and adenylate (ATP, ADP, AMP) levels were analyzed using high-performance liquid chromatography (HPLC) and the energy charge (EC) was calculated. At 15 min post-injury, mildly brain-injured animals showed a 43% decrease in cortical ATP levels and a 2.4-fold increase in AMP levels (P < 0.05), and there was a significant reduction of the ipsilateral cortical EC when compared to sham-injured animals (P < 0.05). At 40 min post-injury, the ipsilateral adenylate levels and EC had recovered to the values observed in the sham-injury group. In the severe CCC group, there was a 51% decrease in ipsilateral cortical ATP levels and a 5.3-fold increase in AMP levels with a significant reduction of cortical EC at 15 min post-injury (P < 0.05). At 40 min post-injury, a 2.6-fold ipsilateral increase in AMP levels and an 11% and 44% decrease in EC and ATP levels, respectively, remained (P < 0.05). A 37-38% reduction of the total adenylate pool was observed ipsilaterally in both CCC severity groups at the early time-point, and a 19% and 28% decrease remained in the mild and severe CCC groups, respectively, at 40 min post-injury. Significant contralateral ATP and EC changes were only observed in the severe CCC group at 40 min post-injury (P < 0.05). The energy-requiring secondary injury cascades that occur early post-injury do not challenge the brain tissue to the extent of ATP depletion and may provide a window of opportunity for therapeutic intervention.

Adenosine Monophosphate↗
PubMed2000

Application of 2,3,5-triphenyltetrazolium chloride staining to evaluate injury volume after controlled cortical impact brain injury: role of brain edema in evolution of injury volume.

A reliable method for measuring injury volume after traumatic brain injury (TBI) is of great importance when studying pharmacological protective agents in the field of head trauma research. Utilization of 2,3,5-triphenyltetrazolium chloride (TTC) has gained extensive acceptance in stroke research and has recently been applied to injury volume measurement in the lateral fluid percussion model. The present study was undertaken to apply this method to the controlled cortical impact (CCI) model and to study the role of brain edema. Male Sprague-Dawley rats were subjected to CCI brain injury at a velocity of 3 m/sec and 1 mm (mild), 2 mm (moderate), and 3 mm (severe injury) deformation, while rats in the control group were subjected to the same surgical procedure but received no injury. Absolute and corrected injury volumes with TTC staining and brain edema measurements with the wet-dry method were evaluated at 1, 2, 3, 4, and 7 days after TBI. The most prominent injury volume in the moderate injury group (2 mm deformation) was seen at postinjury day 1 and 2 (day 1, absolute: 49.1+/-5.6, corrected: 40.5+/-7.9; day 2, absolute: 46+/-6.9, corrected: 40.2+/-10.5), whereas the smallest injury volume was found at postinjury day 7 (absolute: 24.9+/-7, corrected: 27.4+/-7.4). The time course of brain edema studies demonstrates that brain edema formation peaks at postinjury day 1. A statistically significant reduction of injury volume was observed after postinjury day 4. We also observed that due to the presence of brain edema absolute injury volume is more than corrected injury volume in the first 3 days after injury as opposed to injury volume at postinjury day 7. These results suggest that the measurement of injury volume with TTC staining should be corrected for brain edema in the CCI brain injury model.

Animals↗
PubMed1995

Brain injury without head injury. Some physics of automobile collisions with particular reference to brain injuries occurring without physical head trauma.

The classic kinematic formula, a=(v2-v0(2))/2s, relating deceleration to change of velocity and displacement during the change, is used to determine the acceleration experienced by the occupants of motor vehicles (and their heads) during collisions. The displacement, s, of the occupants in the accident can often be determined from the deformation of the wreckage, thus yielding this critical information about potential for brain injury. Data from 15 accidents are assembled and approximate accelerations computed. At the same time medical and neuropsychological data have been obtained for each of the accident victims. These accidents and the associated victims (except for one special case) have been selected because in no case has the victim suffered a direct head-contact injury. Nevertheless, all suffered neurologic and/or neuropsychological injuries typical of patients with closed head trauma. The paper demonstrates that with decelerations from 30 g to more than 200 g yet without skull impacts, brain damage results.

Journal Article↗
PubMed1997

Acute lung injury in isolated traumatic brain injury.

OBJECTIVE: To determine the incidence of acute lung injury (ALI) in comatose patients after isolated traumatic brain injury, to determine whether specific brain lesions diagnosed by cranial computed tomographic scans are associated with ALI, and to determine the outcome of patients with head injuries who developed ALI. METHODS: Descriptive epidemiology and a case-control study using the Traumatic Coma Data Bank was performed to evaluate clinical features and brain lesions associated with ALI in patients with isolated head trauma. Patients with ALI were defined as those who demonstrated a ratio of partial pressure of arterial oxygen to fractional expired oxygen of 300 or less. RESULTS: Twenty of 100 comatose patients developed ALI. Patients with ALI were almost three times more likely to die or survive in a vegetative state (odds ratio, 2.8; 95% confidence interval, 1.6-4.9). Specific anatomic brain lesions diagnosed by cranial computed tomographic scans were not associated with ALI. However, patients with more severe injuries, i.e., large nonevacuated mass lesions, and those with midline shift demonstrated a 10- and 5-fold increased risk of ALI (odds ratio, 9.9; 95% confidence interval, 1.2-217.1; and odds ratio, 5.5; 95% confidence interval, 1.5-20.0). CONCLUSIONS: ALI was common in comatose victims with an isolated traumatic brain injury and was associated with an increased risk of death or a severe neurological morbidity. ALI was associated with the global severity of head injury but not with specific anatomic lesions diagnosed by cranial computed tomographic scans.

Adolescent↗