Treatment Of Traumatic Brain Injury Research Articles

Oxidative Stress in Traumatic Brain Injury.

Traumatic Brain Injury (TBI) remains a major cause of disability worldwide. It involves a complex neurometabolic cascade, including oxidative stress. The products of this manuscript is examining the underlying pathophysiological mechanism, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). This process in turn leads to secondary injury cascade, which includes lipid peroxidation products. These reactions ultimately play a key role in chronic inflammation and synaptic dysfunction in a synergistic fashion. Although there are no FDA approved antioxidant therapy for TBI, there is a number of antioxidant therapies that have been tested and include free radical scavengers, activators of antioxidant systems, inhibitors of free radical generating enzymes, and antioxidant enzymes. Antioxidant therapies have led to cognitive and functional recovery post TBI, and they offer a promising treatment option for patients recovering from TBI. Current major challenges in treatment of TBI symptoms include heterogenous nature of injury, as well as access to timely treatment post injury. The inherent benefits of antioxidant therapies include minimally reported side effects, and relative ease of use in the clinical setting. The current review also provides a highlight of the more studied anti-oxidant regimen with applicability for TBI treatment with potential use in the real clinical setting.

Management and Treatment of Traumatic Brain Injuries.

Traumatic brain injuries (TBI) are one of the main reasons for death in recent years worldwide or globally. They are the number one cause of death for both civilians and military members. It affects how the brain functions and is currently one of the crucial concerns ofglobal public health issues. TBIis increasing worldwide because of the increasing dependency on motorized vehicles and machinery. One of the reasons for TBIis the expanding human population. It is the major cause of death and disability in the world. In young adults around the world, it is the main cause of mortality and morbidity. Its complicated etiology and pathogenesis include primarily primary and secondary injury types. Neuroinflammation is also focused on TBItobe cured. The neuroprotection of the injured brain has received tremendous attention during TBI treatment. In this review, we will first discuss the definition of traumatic brain injury, its causes, and the symptoms experienced by patients of various age groups. Finally, treatment methods and advances in treatment will be discussed. In this review, the aftereffects of traumatic brain damage are also covered. Ferroptosis and choline phospholipids are also emphasized as important components of the treatment of traumatic brain damage in this review.

Mechanism of Progesterone in Treatment of Traumatic Brain Injury Based on Network Pharmacology and Molecular Docking Technology.

BACKGROUND Previous studies have confirmed that progesterone has a protective effect on traumatic brain injury (TBI). In this paper, network pharmacology and molecular docking technology were used to further explore the potential mechanism of progesterone in the treatment of TBI. MATERIAL AND METHODS Based on network pharmacology, potential targets of progesterone for TBI were obtained. The network diagram of interactions between target proteins was established to screen the key targets of progesterone for TBI. The DAVID database was used to analyze its biological function and enrichment pathway, and to explore and determine the biological pathway of progesterone in treating TBI. Molecular docking technology was used to simulate the interaction between progesterone and key target proteins. RESULTS Progesterone can treat TBI by anti-inflammatory action, repairing damaged cell membranes, stabilizing the structure of the blood-brain barrier, alleviating brain edema, reducing neuronal apoptosis, and improving neurological function. The molecular mechanism involves the PI3K/Akt signaling pathway, MAPK signaling pathway, and Ras signaling pathway. CONCLUSIONS Progesterone is a potential clinical treatment for TBI. Exploring the potential targets and pathways of TBI therapy through network pharmacology can provide a direction for subsequent research.

Abietic acid ameliorates neuroinflammation and blood-brain barrier disruption in traumatic brain injury by inhibiting MAPK pathway

Purpose: To investigate the effects of abietic acid (AA) on traumatic brain injury (TBI) in a rat model, and the underlying mechanisms of action.
 Methods: Twenty male Sprague-Dawley (SD) rats were randomly divided into four groups of 5 animals each: Sham, TBI, TBI + AA (14 mg/kg), and TBI + AA (28 mg/kg). Controlled cortical impact (CCI) model was used to induce TBI in rats. Western blot was used to determine the protein levels of Claudin 3, Occludin, ZO-1, Bax, Bcl-2, cleaved-caspase3, p65 NF-κB, p-p65 NF-κB, ERK, p-ERK, JNK, p-JNK, p38 and p-p38, while the expressions of TNF-α, IL-6 and IL-1β were determined using the applicable assay kits. Neurological deficit was assessed based on mNSS and brain water content.
 Results: Treatment with AA significantly reduced TBI-induced blood-brain barrier (BBB) damage, as well as apoptosis and neuroinflammation in a concentration-dependent manner (p < 0.001). The neuroprotective effect of AA was associated with the inhibition of the MAPK signaling pathways and subsequent suppression of NF-κB (p < 0.001).
 Conclusion: Abietic acid serves as a potential novel candidate for the treatment of TBI, and its anti-inflammatory and anti-apoptotic effects are related to the suppression of MAPK signaling pathways. Therefore, abietic acid may serve as a novel candidate for the treatment of TBI in humans.

Feasibility and Utility of a Flexible Outcome Assessment Battery for Longitudinal Traumatic Brain Injury Research: A TRACK-TBI Study.

The effects of traumatic brain injury (TBI) are difficult to measure in longitudinal cohort studies, because disparate pre-injury characteristics and injury mechanisms produce variable impairment profiles and recovery trajectories. In preparation for the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, which followed patients with injuries ranging from uncomplicated mild TBI to coma, we designed a multi-dimensional Flexible outcome Assessment Battery (FAB). The FAB relies on a decision-making algorithm that assigns participants to a Comprehensive (CAB) or Abbreviated Assessment Battery (AAB) and guides test selection across all phases of recovery. To assess feasibility of the FAB, we calculated the proportion of participants followed at 2 weeks (2w) and at 3, 6, and 12 months (3m, 6m, 12m) post-injury who completed the FAB and received valid scores. We evaluated utility of the FAB by examining differences in 6m and 12m Glasgow Outcome Scale-Extended (GOSE) scores between participant subgroups derived from the FAB-enabled versus traditional approach to outcome assessment applied at 2w. Among participants followed at 2w (n = 2094), 3m (n = 1871), 6m (n = 1736), and 12m (n = 1607) post-injury, 95-99% received valid completion scores on the FAB, in full or in part, either in person or by telephone. Level of function assessed by the FAB-enabled approach at 2w was associated with 6m and 12m GOSE scores (proportional odds p < 0.001). These findings suggest that the participant classification methodology afforded by the FAB may enable more effective data collection to improve detection of natural history changes and TBI treatment effects.

Adequacy of Healthcare by Insurance Type in Traumatic Brain Injury Patients

Traumatic brain injury (TBI) is a significant contributor to disability, especially among patients younger than 18 years old in the United States. While insurance is often needed to receive services, studies investigating whether TBI treatment adequacy is dependent on the insurance type are scant. Our objective was to determine whether private insurance in paediatric TBI patients is associated with a higher perceived adequacy of healthcare compared with non-private insurance. This was a cross-sectional study utilising secondary data collected from the National Survey of Children Health 2011/12. The main exposure of interest was the insurance status of children at the time of a TBI (private vs non-private). The study outcome was the perceived adequacy of healthcare, defined as having coverage needs that were usually or always met by insurance. Unadjusted and adjusted logistic regression analysis were used. After adjustments for the covariates, the odds of adequate healthcare among those with non-private insurance compared with those with private were not statistically significant (OR 1.49; 95% CI 0.87–2.55). This study implicates paediatric TBI patients do not believe they receive adequate healthcare independent of insurance status. Clinicians, policy makers, and researchers need to better evaluate and address this issue.

Disparities in Decompressive Cranial Surgery Utilization in Severe Traumatic Brain Injury Patients without a Primary Extra-Axial Hematoma: A U.S. Nationwide Study

Decompressive craniectomy is recommended to reduce mortality in severe traumatic brain injury (TBI). Disparities exist in TBI treatment outcomes; however, data on disparities pertaining to decompressive craniectomy utilization is lacking. We investigated these disparities, focusing on race, insurance, sex, and age. Hospitalizations (2004-2014) were retrospectively extracted from the Nationwide Inpatient Sample. The criteria included are as follows: age ≥18years and indicators of severe TBI diagnosis. Poor outcomes were defined as discharge to institutional care and death. Multivariable logistic regression models were used to assess the effects of race, insurance, age, and sex, on craniectomy utilization and outcomes. Of 349,164 hospitalized patients, 6.8% (n= 23,743) underwent craniectomy. White (odds ratio [OR]=0.50, 95% confidence interval [CI]= 0.44-0.57; P < 0.001) and Black (OR=0.45, 95% CI= 0.32-0.64; P= 0.003) Medicare beneficiaries were less likely to undergo craniectomy. Medicare (P < 0.0001) and Medicaid beneficiaries (P<0.0001) of all race categories had poorer outcomes than privately insured White patients. Black (OR=1.2, 95% CI=1.08-2.34; P=0.001) patients with private insurance and Black (OR=1.39, 95% CI= 1.22-1.58; P<0.0001) Medicaid beneficiaries had poorer outcomes than privately insured White patients (P<0.0001). Older patients (OR=0.74, 95%, CI= 0.71-0.76; P<0.001) were less likely to undergo craniectomy and were more likely to have poorer outcomes. Females (OR=0.82, 95% CI= 0.76-0.88; P<0.001) were less likely to undergo craniectomy. There are disparities in race, insurance status, sex, and age in craniectomy utilization and outcome. This data highlights the necessity to appropriately address these disparities, especially race and sex, and actively incorporate these factors in clinical trial design and enrollment.

Saffron Extract Attenuates Anxiogenic Effect and Improves Cognitive Behavior in an Adult Zebrafish Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) has the highest mortality rates worldwide, yet effective treatment remains unavailable. TBI causes inflammatory responses, endoplasmic reticulum stress, disruption of the blood–brain barrier and neurodegeneration that lead to loss of cognition, memory and motor skills. Saffron (Crocus sativus L.) is known for its anti-inflammatory and neuroprotective effects, which makes it a potential candidate for TBI treatment. Zebrafish (Danio rerio) shares a high degree of genetic homology and cell signaling pathways with mammals. Its active neuro-regenerative function makes it an excellent model organism for TBI therapeutic drug identification. The objective of this study was to assess the effect of saffron administration to a TBI zebrafish model by investigating behavioral outcomes such as anxiety, fear and memory skills using a series of behavioral tests. Saffron exhibited anxiolytic effect on anxiety-like behaviors, and showed prevention of fear inhibition observed after TBI. It improved learning and enhanced memory performance. These results suggest that saffron could be a novel therapeutic enhancer for neural repair and regeneration of networks post-TBI.

Activity of a Novel Anti-Inflammatory Agent F-3,6'-dithiopomalidomide as a Treatment for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6′-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6’-DP. F-3,6′-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6′-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6′-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

Hypoxia-pretreated mesenchymal stem cell-derived exosomes-loaded low-temperature extrusion 3D-printed implants for neural regeneration after traumatic brain injury in canines.

Regenerating brain defects after traumatic brain injury (TBI) still remains a significant difficulty, which has motivated interest in 3D printing to design superior replacements for brain implantation. Collagen has been applied to deliver cells or certain neurotrophic factors for neuroregeneration. However, its fast degradation rate and poor mechanical strength prevent it from being an excellent implant material after TBI. In the present study, we prepared 3D-printed collagen/silk fibroin/hypoxia-pretreated human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomes scaffolds (3D-CS-HMExos), which possessed favorable physical properties suitable biocompatibility and biodegradability and were attractive candidates for TBI treatment. Furthermore, inspired by exosomal alterations resulting from cells in different external microenvironments, exosomes were engineered through hypoxia stimulation of mesenchymal stem cells and were proposed as an alternative therapy for promoting neuroregeneration after TBI. We designed hypoxia-preconditioned (Hypo) exosomes derived from HUCMSCs (Hypo-MExos) and proposed them as a selective therapy to promote neuroregeneration after TBI. For the current study, 3D-CS-HMExos were prepared for implantation into the injured brains of beagle dogs. The addition of hypoxia-induced exosomes further exhibited better biocompatibility and neuroregeneration ability. Our results revealed that 3D-CS-HMExos could significantly promote neuroregeneration and angiogenesis due to the doping of hypoxia-induced exosomes. In addition, the 3D-CS-HMExos further inhibited nerve cell apoptosis and proinflammatory factor (TNF-α and IL-6) expression and promoted the expression of an anti-inflammatory factor (IL-10), ultimately enhancing the motor functional recovery of TBI. We proposed that the 3D-CS-loaded encapsulated hypoxia-induced exosomes allowed an adaptable environment for neuroregeneration, inhibition of inflammatory factors and promotion of motor function recovery in TBI beagle dogs. These beneficial effects implied that 3D-CS-HMExos implants could serve as a favorable strategy for defect cavity repair after TBI.

Self-Awareness and therapeutic alliance in speech-language treatment of traumatic brain injury

Purpose: To investigate the relationships among client self-awareness, client perception of the therapeutic alliance, and speech-language pathologist (SLP) communicative self-awareness in dyads of SLPs and traumatic brain injury (TBI) clients. Method: Nineteen SLP-TBI client dyads (N = 38) engaged in the same collaborative therapy task. At baseline, client self-awareness and client perception of the therapeutic alliance was assessed. SLP communicative self-awareness was measured by 1) a prediction/reflection questionnaire about their own communicative behaviour, administered pre- and post-treatment sessions, and 2) self-evaluation during a novel procedure using video review within three hours after the session. Result: Client self-awareness was not associated with client perceptions of the therapeutic alliance. Client perceptions of the therapeutic alliance were related to specific communicative intentions of the SLP. Regarding SLP communicative self-awareness, SLPs predicted their primary communication modality with 66% accuracy. The video review procedure yielded more detailed SLP communicative self-awareness ratings and was completed within real-world clinical settings. Conclusion: TBI client self-awareness may not impact the establishment of a strong therapeutic alliance between SLP and client. The finding that specific communicative intentions of the SLP were related to client perception of the therapeutic alliance should prompt further efforts to measure SLP communicative intentions and behaviours during TBI treatment sessions.

The S-100B level, intracranial pressure, body temperature, and transcranial blood flow velocities predict the outcome of the treatment of severe brain injury.

This study evaluates the applicability of S100B levels, mean maximum velocity (Vmean) over time, pulsatility index (PI), intracranial pressure (ICP), and body temperature (T) for the prediction of the treatment of patients with traumatic brain injury (TBI). Sixty patients defined by the Glasgow Coma Scale score ≤ 8 were stratified using the Glasgow Coma Scale into 2 groups: favorable (FG: Glasgow Outcome Scale ≥ 4) and unfavorable (UG: Glasgow Outcome Scale < 4). The S100B concentration was at the time of hospital admission. Vmean was measured using transcranial Doppler. PI was derived from a transcranial Doppler examination. T was measured in the temporal artery. The differences in mean between FG and UG were tested using a bootstrap test of 10,000 repetitions with replacement. Changes in S100B, Vmean, PI, ICP, and T levels stratified by the group were calculated using the one-way aligned rank transform for nonparametric factorial analysis of variance. The reference ranges for the levels of S100B, Vmean, and PI were 0.05 to 0.23 µg/L, 30.8 to 73.17 cm/s, and 0.62 to 1.13, respectively. Both groups were defined by an increase in Vmean, a decrease in S100B, PI, and ICP levels; and a virtually constant T. The unfavorable outcome is defined by significantly higher levels of all parameters, except T. A favorable outcome is defined by S100B < 3 mg/L, PI < 2.86, ICP > 25 mm Hg, and Vmean > 40 cm/s. The relationships provided may serve as indicators of the results of the TBI treatment.

Hyaluronic acid extracellularly inhibits ferroptosis via cell-surface receptors in acute traumatic brain injury

Traumatic brain injury (TBI) is an important cause of death and disability in young people worldwide without effective treatment. Ferroptosis was recently reported to be related to TBI and provided a potential target for developing new therapeutic strategies, but how it influenced TBI and the underlying mechanism were still unclear. Here, with multimodality of methods, ferroptosis was demonstrated to mainly occur in acute TBI. Further, we found that hyaluronic acid (HA), a natural extracellular matrix (ECM) material, could markedly and specifically inhibit ferroptosis in cells and TBI mice. Preblocking the HA-receptor interaction or CRISPR/Cas9-based gene deletion of HA putative receptors neurocan (NCN) and CD44 abolished the anti-ferroptosis effect of HA. Importantly, it was demonstrated that CD44 was significantly up regulated by tens of folds in the focus area of TBI. Through intravenous injection of Cy5-HA nanoconjugates, it was shown that HA could effectively bind to the TBI site like a targeting nanodrug and then, significantly reduced brain damage and behavioral defects. Collectively, we demonstrated HA as the natural anti-ferroptosis material which acted through receptor-mediated intrinsic signaling pathways, and developed a new therapeutic avenue for acute TBI treatment. Moreover, the new function of HA revealed in the study confirmed the existence of extracellular regulation of ferroptosis, and would largely promote the development of novel nanomaterials or nanodrugs for ferroptosis-related tissue injuries.

Dexamethasone-Loaded Hydrogels Improve Motor and Cognitive Functions in a Rat Mild Traumatic Brain Injury Model.

Functional recovery following traumatic brain injury (TBI) is limited due to progressive neuronal damage resulting from secondary injury-associated neuroinflammation. Steroidal anti-inflammatory drugs, such as dexamethasone (DX), can reduce neuroinflammation by activated microglia and infiltrated macrophages. In our previous work, we developed hydrolytically degradable poly(ethylene) glycol-bis-(acryloyloxy acetate) (PEG-bis-AA) hydrogels with dexamethasone (DX)-conjugated hyaluronic acid (HA-DXM) and demonstrated that dexamethasone-loaded hydrogels (PEG-bis-AA/HA-DXM) can reduce neuroinflammation, apoptosis, and lesion volume and improve neuronal cell survival and motor function recovery at seven days post-injury (DPI) in a rat mild-TBI model. In this study, we investigate the effects of the local application of PEG-bis-AA/HA-DXM hydrogels on motor function recovery at 7 DPI and cognitive functional recovery as well as secondary injury at 14 DPI in a rat mild-CCI TBI model. We observed that PEG-bis-AA/HA-DXM-treated animals exhibit significantly improved motor functions by the rotarod test and cognitive functions by the Morris water maze test compared to untreated TBI animals. We also observed that PEG-bis-AA/HA-DXM hydrogels reduce the inflammatory response, apoptosis, and lesion volume compared to untreated animals at 14 DPI. Therefore, PEG-bis-AA/HA-DXM hydrogels can be promising a therapeutic intervention for TBI treatment.

Evaluation of Post-Hospital Care of Traumatic Brain Injury in Children, Adolescents and Young Adults-A Survey among General Practitioners and Pediatricians in Germany.

Background: The long-term effects of mild Traumatic Brain Injury (TBI) in children and adolescents are increasingly discussed due to their potential impact on psycho-social development and education. This study aims to evaluate post-hospital care of children and adolescents after mild TBI using a physician survey. Methods: A self-developed, pre-tested questionnaire on diagnostics and treatment of TBI in outpatient care was sent to a representative sample of general practitioners and pediatricians in Germany. Results: Datasets from 699 general practitioners, 334 pediatricians and 24 neuropediatricians were available and included in the analysis. Nearly half of the general practitioners and most pediatricians say they treat at least one acute pediatric TBI per year. However, a substantive proportion of general practitioners are not familiar with scales assessing TBI severity and have difficulties assessing the symptoms correctly. Pediatricians seem to have better knowledge than general practitioners when it comes to treatment and outpatient care of TBI. Conclusions: To increase knowledge about TBI in outpatient physicians, targeted training courses should be offered, especially for general practitioners. Moreover, handing out written information about long-term effects and reintegration after TBI should be encouraged in outpatient practice.

Systematic Analysis of tRNA-Derived Small RNAs Reveals the Effects of Xuefu-Zhuyu Decoction on the Hippocampi of Rats after Traumatic Brain Injury.

Background Traumatic brain injury (TBI) is one of the most common neurosurgical diseases and refers to brain function impairment or brain pathological changes induced by external causes. A traditional Chinese medicine, Xuefu-Zhuyu Decoction (XFZYD), has been indicated to harbor therapeutic properties against TBI. Transfer RNA (tRNA)-derived small RNAs, that is, tsRNAs (a group of small RNAs derived from tRNAs), are multifunctional regulatory noncoding RNAs generated under pressure and implicated in the progression of TBI. Methods A TBI model was successfully constructed using rats. We further performed sequencing and omics analyses to identify novel tsRNAs as drug targets for XFZYD therapy against TBI in the rat hippocampus. qPCR assays were used to further verify the experimental results. Gene Ontology (GO) was used to analyze the signaling pathways of downstream target genes of tsRNAs in the XFZYD-regulated TBI model. qPCR was used to detect the influence of overexpressed tsRNA mimics/inhibitors on their target genes in PC12 cells. Results Our RNA-Seq data illustrate that 11 tsRNAs were mediated by XFZYD. The experimental data revealed AS-tDR-002004 and AS-tDR-002583 as potential targets for XFZYD therapy and showed that they influenced TBI via the cadherin signaling pathway, cocaine addiction, circadian entrainment, and the nicotine pharmacodynamics pathway. We also confirmed that Pi4kb, Mlh3, Pcdh9, and Ppp1cb were target genes of 2 XFZYD-regulated tsRNAs in the hippocampus of a rat model and PC12 cells. Furthermore, biological function analysis revealed the potential therapeutic effects of tsRNAs, and the results showed that Mapk1 and Gnai1 were related genes for XFZYD therapy against TBI. Conclusion Our work successfully illuminates the efficiency of XFZYD in the treatment of TBI. The experimental data revealed AS-tDR-002004 and AS-tDR-002583 as potential targets for XFZYD therapy and showed that they influenced TBI via the cadherin signaling pathway, cocaine addiction, circadian entrainment, and the nicotine pharmacodynamics pathway in a TBI rat model.

Paired associates learning is disrupted after unilateral parietal lobe controlled cortical impact in rats: A trial-by-trial behavioral analysis

Approximately 60–70 million people suffer from traumatic brain injury (TBI) each year. Animal models continue to be paramount in understanding mechanisms of cellular dysfunction and testing new treatments for TBI. Enhancing the translational potential of novel interventions therefore necessitates testing pre-clinical intervention strategies with clinically relevant cognitive assays. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based Paired Associates Learning (PAL) task, which is part of the Cambridge Neuropsychological Test Automated Battery. In humans, the PAL task has been used to assess cognitive deficits in the ability to form stimulus-location associations in a multitude of disease states, including TBI. Although the use of PAL in animal models could be important for understanding the clinical severity of cognitive impairment post-injury and throughout intervention, to date, the extent to which a rat model of TBI produces deficits in PAL task performance has not yet been reported. This study details the behavioral consequences of the CCI injury model with a Trial-by-Trial analysis of PAL performance that enables behavioral strategy use to be inferred. Following behavior, the extent of the injury was quantified with histology and staining for the presence of glial fibrillary acid protein and ionized calcium-binding adapter molecule 1. Rats that received unilateral CCI were impaired on the PAL task and showed more aberrant response-driven behavior. The magnitude of PAL impairment was also correlated with Iba1 staining in the thalamus. These observations suggest that PAL could be useful for pre-clinical assessments of novel interventions for treating TBI.

Stem Cell Therapy for Sequestration of Traumatic Brain Injury-Induced Inflammation.

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn into a “reactive” state, characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Other injuries to the brain, including radiation exposure, may trigger TBI-like pathology, characterized by inflammation. Currently there are no treatments to prevent or reverse the deleterious consequences of brain trauma. The recognition that TBI predisposes stem cell alterations suggests that stem cell-based therapies stand as a potential treatment for TBI. Here, we discuss the inflamed brain after TBI and radiation injury. We further review the status of stem cells in the inflamed brain and the applications of cell therapy in sequestering inflammation in TBI.

EFFECTS OF PROGENITOR CELL CONDITIONED MEDIA ON THE AMOUNT OF BRAIN CORTEX NEURONS IN A RAT MODEL OF TRAUMATIC BRAIN INJURY

Aim. The purpose of the study was to examine beneficial effect of conditioned media (CM) of progenitor cells of different origin (neurogenic progenitor cells, or NPCs, and adipose-derived mononuclear cells, or AMCs) as a source of mesenchymal multipotent stromal cells (MMSCs) on brain cortex neurons in rats with traumatic brain injury (TBI). Methods. TBI was reproduced in outbred sexually mature male rats by developing the model of free-falling load (50 g) with damage to the left hemisphere of the brain. The rats were injected 3 times with an interval of every other day intraperitoneally with NPCs CM and AMCs CM (dose 0.8 mg by total protein) that were obtained from cell cultures of fetal rat brain and adult rat adipose tissue. On the 5th day after TBI, the morphologic study of brain tissue was performed. Results. The number of neurons in the cortex of rats on the 5th day after TBI in damaged hemisphere as well as in contralateral hemisphere compared to control group decreased by half. Three i.p. injections of NPCs CM or AMCs CM increased the number of neurons in the cortex in both hemispheres in rats of corresponding groups compared to the rats with TBI without additional treatment. Conclusion. Obtained results indicate that CM obtained from NPCs and AMCs have noticeable neuroprotective effect on the damaged neurons and might be considered as an additional mode to treatment of TBI.

Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and young adults in the United States. In this manuscript, we assessed the utility of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug (P-Dex) in the treatment of TBI. Using a controlled cortical impact TBI mouse model, P-Dex was found to passively target and sustain at the traumatic/inflammatory brain tissue for over 14 days after systemic administration. The histological evidence supports P-Dex's therapeutic potential in ameliorating neuroinflammation and mitigating neurodegeneration. Behaviorally, the P-Dex-treated animals showed statistically significant improvement in balance recovery. A trend of neurological severity score improvement at the early time point post-TBI was also noted but did not achieve statistical significance. While probing the potential glucocorticoid side effects that may associate with P-Dex treatment, we discovered that the TBI mice develop osteopenia. Interestingly, the P-Dex-treated TBI mice demonstrated higher bone mineral density and better bone microarchitecture parameters when compared to free Dex and the saline control, revealing the osteoprotective effect of P-Dex in addition to its neuronal protection benefits post-TBI.