Role In Traumatic Brain Injury Research Articles

Potential Neuroprotective Role of Neurotrophin in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major global health issue that affects millions of people every year. It is caused by any form of external force, resulting in temporary or permanent impairments in the brain. The pathophysiological process following TBI usually involves excitotoxicity, mitochondrial dysfunction, oxidative stress, inflammation, ischemia, and apoptotic cell death. It is challenging to find treatment for TBI due to its heterogeneous nature, and no therapeutic interventions have been approved thus far. Neurotrophins may represent an alternative approach for TBI treatment because they influence various functional activities in the brain. The present review highlights recent studies on neurotrophins shown to possess neuroprotective roles in TBI. Neurotrophins, specifically brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have demonstrated reduced neuronal death, alleviated neuroinflammatory responses and improved neurological functions following TBI via their immunomodulatory, anti-inflammatory and antioxidant properties. Further studies are required to ensure the efficacy and safety of neurotrophins to be used as TBI treatment in clinical settings.

Quercetin alleviates microglial-induced inflammation after traumatic brain injury via the PGC-1α/Nrf2 pathway dependent on HDAC3 inhibition

Inflammation and neuronal apoptosis play a key role in traumatic brain injury (TBI). Quercetin (Que) has been shown to exhibit a neuroprotective effect after TBI, but the underlying molecular mechanism remains unclear. In this study, We established a weight-drop mouse model to illustrate the effects of Que on microglial-induced inflammation in TBI. Mice were divided into four groups: the Sham group, TBI group, TBI+vehicle group, and TBI+Que group. The TBI+Que group was treated with Que 30 min after TBI. Brain water content, neurological score, and neuronal apoptosis were measured. Western blotting, TUNEL staining, Nissl staining, quantitative polymerase chain reaction, and immunofluorescence staining were performed to assess the activation of the PGC-1α/Nrf2 pathway and nuclear translocation of HDAC3 with Que treatment. The results showed that Que administration alleviated TBI-induced neurobehavioral deficits, encephaledema, and neuron apoptosis. Que also restrained TBI-induced microglial activity and the subsequent expression of the inflammatory factor in the contusion cortex. Moreover, Que treatment activated the PGC-1α/Nrf2 pathway, attributable to the inhibition of HDAC3 translocation to the nucleus. Overall, these results reveal the role of Que in protecting against TBI-induced neuroinflammation and promoting neurological functional recovery, which is achieved through the negative regulation of HDAC3.

SCG2 mediates blood-brain barrier dysfunction and schizophrenia-like behaviors after traumatic brain injury.

Traumatic brain injury (TBI), which is characterized by acute neurological dysfunction, is also one of the most widely recognized environmental risk factors for various neurological and psychiatric disorders. However, the role of TBI in neurological perturbation and the mechanisms underlying these disorders remain unknown. We evaluated transcriptional changes in cells of the frontal cortex after TBI by exploiting single-cell RNA sequencing (scRNA-Seq). We adopted the gene expression omnibus and scRNA-Seq to identify the mediation by secretogranin II (SCG2) of TBI-induced schizophrenia. Astrocytes are a principal source of SCG2 in the frontal cortex after TBI. Our analysis indicated that SCG2-triggered disruption of the blood-brain barrier (BBB) via the CypA-MMP-9 signaling pathway. Furthermore, astrocytic SCG2 knockout in the frontal cortex reduced BBB damage, mitigated inflammation, and inhibited schizophrenia after TBI. In conclusion, we identified the SCG2-CypA-MMP-9 signaling pathway in reactive astrocytes as a key switch in the protection of the BBB and provided a novel therapeutic avenue for treating psychiatric disorders after TBI.

Traumatic brain injury and sleep in military and veteran populations: A literature review.

Traumatic brain injury (TBI) is a hallmark of wartime injury and is related to numerous sleep wake disorders (SWD), which persist long term in veterans. Current knowledge gaps in pathophysiology have hindered advances in diagnosis and treatment. We reviewed TBI SWD pathophysiology, comorbidities, diagnosis and treatment that have emerged over the past two decades. We conducted a literature review of English language publications evaluating sleep disorders (obstructive sleep apnea, insomnia, hypersomnia, parasomnias, restless legs syndrome and periodic limb movement disorder) and TBI published since 2000. We excluded studies that were not specifically evaluating TBI populations. Highlighted areas of interest and knowledge gaps were identified in TBI pathophysiology and mechanisms of sleep disruption, a comparison of TBI SWD and post-traumatic stress disorder SWD. The role of TBI and glymphatic biomarkers and management strategies for TBI SWD will also be discussed. Our understanding of the pathophysiologic underpinnings of TBI and sleep health, particularly at the basic science level, is limited. Developing an understanding of biomarkers, neuroimaging, and mixed-methods research in comorbid TBI SWD holds the greatest promise to advance our ability to diagnose and monitor response to therapy in this vulnerable population.

Targeting astrocytic TDAG8 with delayed CO2 postconditioning improves functional outcomes after controlled cortical impact injury in mice

T-cell death-associated gene 8 (TDAG8), a G-protein-coupled receptor sensing physiological or weak acids, regulates inflammatory responses. However, its role in traumatic brain injury (TBI) remains unknown. Our recent study showed that delayed CO2 postconditioning (DCPC) has neuroreparative effects after TBI. We hypothesized that activating astrocytic TDAG8 is a key mechanism for DCPC. WT and TDAG8−/− mice received DCPC daily by transiently inhaling 10% CO2 after controlled cortical impact (CCI). HBAAV2/9-GFAP-m-TDAG8-3xflag-EGFP was used to overexpress TDAG8 in astrocytes. The beam walking test, mNSS, immunofluorescence and Golgi-Cox staining were used to evaluate motor function, glial activation and dendritic plasticity. DCPC significantly improved motor function; increased total dendritic length, neuronal complexity and spine density; inhibited overactivation of astrocytes and microglia; and promoted the expression of astrocytic brain-derived neurotrophic factor in WT but not TDAG8−/− mice. Overexpressing TDAG8 in astrocytes surrounding the lesion in TDAG8−/− mice restored the beneficial effects of DCPC. Although the effects of DCPC on Days 14–28 were much weaker than those of DCPC on Days 3–28 in WT mice, these effects were further enhanced by overexpressing astrocytic TDAG8. Astrocytic TDAG8 is a key target of DCPC for TBI rehabilitation. Its overexpression is a strategy that broadens the therapeutic window and enhances the effects of DCPC.

Copeptin's role in traumatic brain injury: The promising quest for a new biomarker

ObjectiveTraumatic brain injury (TBI) necessitates reliable biomarkers to improve patient care. This study explored copeptin as a potential biomarker in TBI and its relation to vasopressin (ADH) in such patients. MethodsA cross-sectional study was conducted on 50 TBI patients. Exclusion criteria included specific medical conditions and recent traumatic events. Copeptin and ADH testing were performed within 30 days post-trauma. Patient data, Glasgow Coma Scale (GCS) scores, imaging results, and the need for surgical intervention were obtained from medical charts. ResultsCopeptin levels negatively correlated with GCS scores (ρ = − 0.313, p = 0.027), indicating a potential association with trauma severity. Copeptin levels (mean: 3.22 pmol/L, median 2.027 pmol/L, SD = 3.15) tended to be lower than those found in the normal population, suggesting possible neuroendocrine dysfunction post-TBI. ADH levels (mean: 67.93 pmol/L, median 56.474 pmol/L SD = 47.67) were higher than the normal range and associated with the need for surgery (p = 0.048). Surprisingly, copeptin and ADH levels negatively correlated (r = − 0.491; p < 0.001), potentially due to differences in degradation processes and physiological variations in TBI patients. ConclusionCopeptin shows potential as a predictive biomarker for assessing TBI severity and predicting patient outcome. However, its complex relationship with ADH in TBI requires further investigation. Careful interpretation is needed due to potential variations in excretion dynamics and metabolism. Larger studies on TBI patient cohorts are essential to validate copeptin as a reliable biomarker and improve patient care in TBI.

Epigallocatechin-3-gallate loaded proliposomal vesicles for management of traumatic brain injury: In-vitro and in-vivo evaluation

One of the primary causes of disability and mortality worldwide is traumatic brain injury (TBI). Oxidative stress is one of the main pathological cascades of TBI. Therefore, finding an effective antioxidant for TBI is a challenge. Several studies revealed that Epigallocatechin-3-gallate (EGCG) had neuroprotective properties, so it might play an important role in TBI. However, it has some drawbacks including instability that may lead to reduced efficacy which could be enhanced using nanoformulation. Consequently, this study aimed to design and optimize EGCG-loaded Proliposomes (EGCG-PLs) and to investigate the antioxidant effect against TBI in rats by modulating the Sirt1/Nrf2/HO-1 signaling pathway. EGCG-PLs were formulated by the slurry technique. Then, to choose the best formula, nanovesicles were assessed and optimized by the Box-Behnken Design to determine the effect of preparation factors on the formed vesicles. Following that, we used an animal model of TBI to compare the neuroprotective effects of the optimized formula to the free drug in vivo. To confirm the neuroprotective action, oxidative stress biomarkers were evaluated as well as histopathological examinations of different brain tissues were performed. The optimized EGCG-loaded PLs formula had a mean size of 150.63 ± 2.65 nm while the percentage of entrapment efficiency was 89.744 ± 0.89 %. The EGCG in vitro release from the optimized PLs formula was prolonged in comparison with the free EGCG. The optimized formula showed a superior antioxidant effect compared to its free counterpart as it significantly decreased MDA and increased the endogenous antioxidants, SOD, and GSH, of brain tissues in addition to activation of the Sirt1/Nrf2/HO-1 signaling pathway. Furthermore, amelioration of histopathological alterations induced by TBI in brain tissues was more prominent with EGCG-PLs treatment. To conclude, all outcomes point to a potential enhancement in the efficacy of EGCG when prepared in PLs in combating TBI.

The bibliometric analysis on neural stem cells in the treatment of traumatic brain injury

Background: Traumatic brain injury (TBI) is caused by a blow or a penetrating injury to the head, which can disrupt normal brain function and is life-threatening to the patient. Neural stem cells can play a certain neuroprotective role in TBI with its enormous self-renewal and differentiation capacity. Therefore, this paper reviews the research progress of neural stem cells in the treatment of TBI based on bibliometric analysis. Methods: Web of Science Core Collection database was used according to the search formula TS = ("Neural stem cell") AND TS = ("Traumatic Brain Injury") AND Publication Date = (January 1, 2001 to December 31, 2023) to find 174 relevant articles. Subsequently, bibliometrics analysis was performed to know the contributions of countries, institutions, journals, and current trends and research hotspots by using Vosviewer and Citespace software. Results: The results suggest that the current research trend in neural stem cell treatment of TBI is focusing on neurogenesis. The most influential countries are the United States, China, and Japan with the highest publications. The impactful institutions and authors are also distributed among these countries. Conclusions: This review summarizes the current advances in neural stem cell treatment of TBI, which is helpful for future research guidance.

Association of Cadherin-Related Family Member 1 with Traumatic Brain Injury

The cadherin family plays a pivotal role in orchestrating synapse formation in the central nervous system. Cadherin-related family member 1 (CDHR1) is a photoreceptor-specific calmodulin belonging to the expansive cadherin superfamily. However, its role in traumatic brain injury (TBI) remains largely unknown. CDHR1 expression across various brain tissue sites was analyzed using the GSE104687 dataset. Employing a summary-data-based Mendelian Randomization (SMR) approach, integrated analyses were performed by amalgamating genome-wide association study abstracts from TBI with public data on expressed quantitative trait loci and DNA methylation QTL from both blood and diverse brain tissues. CDHR1 expression and localization in different brain tissues were meticulously delineated using western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay. CDHR1 expression was consistently elevated in the TBI group compared to that in the sham group across multiple tissues. The inflammatory response emerged as a crucial biological mechanism, and pro-inflammatory and anti-inflammatory factors were not expressed in either group. Integrated SMR analyses encompassing both blood and brain tissues substantiated the heightened CDHR1 expression profiles, with methylation modifications emerging as potential contributing factors for increased TBI risk. This was corroborated by western blotting and immunohistochemistry, confirming augmented CDHR1 expression following TBI. This multi-omics-based genetic association study highlights the elevated TBI risk associated with CDHR1 expression coupled with putative methylation modifications. These findings provide compelling evidence for future targeted investigations and offer promising avenues for developing interventional therapies for TBI.Graphical Cadherin-related family member 1 as a potential risk factor for traumatic brain injury.

Preso enhances mGluR1-mediated excitotoxicity by modulating the phosphorylation of mGluR1-Homer1 complex and facilitating an ER stress after traumatic brain injury

Glutamate receptor (GluR)-mediated excitotoxicity is an important mechanism causing delayed neuronal injury after traumatic brain injury (TBI). Preso, as a core scaffolding protein of postsynaptic density (PSD), is considered an important regulator during excitotoxicity and TBI and combines with glutamate receptors to form functional units for excitatory glutamatergic neurotransmission, and elucidating the mechanisms of these functional units will provide new targets for the treatment of TBI. As a multidomain scaffolding protein, Preso directly interacts with metabotropic GluR (mGluR) and another scaffold protein, Homer. Because the mGluR-Homer complex plays a crucial role in TBI, modulation of this complex by Preso may be an important mechanism affecting the excitotoxic damage to neurons after TBI. Here, we demonstrate that Preso facilitates the interaction between metabotropic mGluR1 and Homer1 to activate mGluR1 signaling and cause excitotoxic neuronal injury and endoplasmic reticulum (ER) stress after TBI. The regulatory effect of Preso on the mGluR1-Homer1 complex is dependent on the direct association between Preso and this complex and also involves the phosphorylation of the interactive binding sites of mGluR1 and Homer1 by Preso. Further studies confirmed that Preso, as an adaptor of cyclin-dependent kinase 5 (CDK5), promotes the phosphorylation of the Homer1-binding site on mGluR1 by CDK5 and thereby enhances the interaction between mGluR1 and Homer1. Preso can also promote the formation of the mGluR1-Homer1 complex by inhibiting the phosphorylation of the Homer1 hinge region by Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα). Based on these molecular mechanisms, we designed several blocking peptides targeting the interaction between Preso and the mGluR1-Homer1 complex and found that directly disrupting the association between mGluR1 and scaffolding proteins significantly promotes the recovery of motor function after TBI.

Armcx1 Reduces Neurological Damage Via a Mitochondrial Transport Pathway Involving Miro1 After Traumatic Brain Injury

Armcx1 is a member of the ARMadillo repeat-Containing protein on the X chromosome (ARMCX) family, which is recognized to have evolutionary conserved roles in regulating mitochondrial transport and dynamics. Previous research has shown that Armcx1 is expressed at higher levels in mice after axotomy and in adult retinal ganglion cells after crush injury, and this protein increases neuronal survival and axonal regeneration. However, its role in traumatic brain injury (TBI) is unclear. Therefore, the aim of this study was to assess the expression of Armcx1 after TBI and to explore possible related mechanisms by which Armcx1 is involved in TBI. We used C57BL/6 male mice to model TBI and evaluated the role of Armcx1 in TBI by transfecting mice with Armcx1 small interfering RNA (siRNA) to inhibit Armcx1 expression 24 h before TBI modeling. Western blotting, immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, Nissl staining, transmission electron microscopy, adenosine triphosphate (ATP) level measurement, neuronal apoptosis analysis, neurological function scoring and the Morris water maze were performed. The results demonstrated that Armcx1 protein expression was elevated after TBI and that the Armcx1 protein was localized in neurons and astroglial cells in cortical tissue surrounding the injury site. In addition, inhibition of Armcx1 expression further led to impaired mitochondrial transport, abnormal morphology, reduced ATP levels, aggravation of neuronal apoptosis and neurological dysfunction, and decrease Miro1 expression. In conclusion, our findings indicate that Armcx1 may exert neuroprotective effects by ameliorating neurological injury after TBI through a mitochondrial transport pathway involving Miro1.

Progesterone induces neuroprotection associated with immune/inflammatory modulation in experimental traumatic brain injury.

An imbalance of immune/inflammatory reactions aggravates secondary brain injury after traumatic brain injury (TBI) and can deteriorate clinical prognosis. So far, not enough therapeutic avenues have been found to prevent such an imbalance in the clinical setting. Progesterone has been shown to regulate immune/inflammatory reactions in many diseases and conveys a potential protective role in TBI. This study was designed to investigate the neuroprotective effects of progesterone associated with immune/inflammatory modulation in experimental TBI. A TBI model in adult male C57BL/6J mice was created using a controlled contusion instrument. After injury, the mice received consecutive progesterone therapy (8 mg/kg per day, i.p.) until euthanized. Neurological deficits were assessed via Morris water maze test. Brain edema was measured via the dry-wet weight method. Immunohistochemical staining and flow cytometry were used to examine the numbers of immune/inflammatory cells, including IBA-1 + microglia, myeloperoxidase + neutrophils, and regulatory T cells (Tregs). ELISA was used to detect the concentrations of IL-1β, TNF-α, IL-10, and TGF-β. Our data showed that progesterone therapy significantly improved neurological deficits and brain edema in experimental TBI, remarkably increased regulatory T cell numbers in the spleen, and dramatically reduced the activation and infiltration of inflammatory cells (microglia and neutrophils) in injured brain tissue. In addition, progesterone therapy decreased the expression of the pro-inflammatory cytokines IL-1β and TNF-α but increased the expression of the anti-inflammatory cytokine IL-10 after TBI. These findings suggest that progesterone administration could be used to regulate immune/inflammatory reactions and improve outcomes in TBI.

Network pharmacology and molecular docking-based investigation of monocyte locomotion inhibitory factor attenuates traumatic brain injury by regulating aquaporin 4 expression.

Traumatic brain injury (TBI) is a significant cause of disability and mortality worldwide, and effective treatment options are currently limited. Monocyte locomotion inhibitor factor (MLIF), a small molecular pentapeptide, has demonstrated a protective effect against cerebral ischemia. This study aimed to investigate the protective effects of MLIF on TBI and explore its underlying mechanism of action. In animal experiments, we observed that administration of MLIF after TBI reduced brain water content and improved brain edema, suggesting a certain degree of protection against TBI. By utilizing network pharmacology methodologies, we employed target screening techniques to identify the potential targets of MLIF in the context of TBI. As a result, we successfully enriched ten signaling pathways that are closely associated with TBI. Furthermore, using molecular docking techniques, we identified AQP4 as one of the top ten central genes discovered in this study. Eventually, our study demonstrated that MLIF exhibits anti-apoptotic properties and suppresses the expression of AQP4 protein, thus playing a protective role in traumatic brain injury. This conclusion was supported by TUNEL staining and the evaluation of Bcl-2, Bax, and AQP4 protein levels. These discoveries enhance our comprehension of the mechanisms by which MLIF exerts its protective effects and highlight its potential as a promising therapeutic intervention for TBI treatment.

Platelet-to-lymphocyte ratio as a prognostic predictive marker on adults with traumatic brain injury: Systematic review.

The platelet-to-lymphocyte ratio (PLR) has emerged as a prognostic predictive marker in various diseases, but its role in traumatic brain injury (TBI) has not been fully elucidated. This study aims to evaluate the role of PLR as a prognostic predictive marker in adults with TBI. This systematic review was conducted according to the Preferred Reporting Items in the Systematic Review and Meta-analysis Guidelines 2020. A comprehensive search was performed using PubMed, Google Scholar, Scopus, Crossref, OpenAlex, Semantic Scholar, Library of Congress, and Jisc Library Hub Discover database to identify relevant studies published up to February 2023. Both prospective and retrospective observational studies written in English or Indonesian were included in the study. No restrictions were placed on the year and country of publication and duration of follow-up. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS), and the risk of bias was estimated using the Cochrane Risk of Bias Assessment Tool for Nonrandomized Research (Ro-BANS) tool. A narrative synthesis was also conducted to summarize the findings. We retrieved 1644 references using the search strategy, and 1623 references were excluded based on screening the title and abstract. The full text was retrieved for 20 articles and subjected to the eligibility criteria, of which 16 were excluded from the study. Four papers with a total of 1.467 sample sizes were included in the review. The median of NOS for study quality was 8-9, with the risk of selection bias using the Ro-BANS tool being low in all studies except for the blinding outcome assessments, which are all unclear. The study finding suggests that the PLR has the potential as an independent prognostic predictive marker in adult patients with TBI. In three studies, a high level of admission PLR may independently predict an increasing mortality risk in 30 days and adverse outcomes measured by the Glasgow outcome scale in 6 months following TBI. However, one study shows that PLR may have limited value as a predictor of mortality or favorable neurological outcomes compared to other hematological parameters. Further studies were needed to establish the clinical utility of PLR and fill the present gaps. This systematic review provides evidence supporting the utilization of PLR as a prognostic predictive marker in adult patients with TBI. The PLR can mainly be utilized, especially in rural practice, as PLR is a simple, low-cost, and routinely performed hematological examination.

Deferoxamine Induces Autophagy Following Traumatic Brain Injury via TREM2 on Microglia.

Previous studies have indicated that iron disorder, inflammation, and autophagy play an important role in traumatic brain injury (TBI). The triggering receptor expressed on myeloid cells 2 (TREM2), an immunoglobulin superfamily transmembrane receptor, is involved in inflammation. However, the role of TREM2 in modulating the microglia response in TBI has been rarely investigated. The present study aimed to investigate if the iron chelator deferoxamine (DFO) could ameliorate TBI through autophagy mediated by the TREM2. TBI was developed by the controlled cortical impact (CCI) mouse model and stretching of individual primary cortical microglia taken from the tissue of the rat brain. DFO was intraperitoneally used for intervention. Western blotting assay, qRT-PCR, TUNEL staining, immunofluorescence staining, confocal microscopy analysis, transmission electron microscopy, H&E staining, brain water content measurement, and the neurobehavioral assessments were performed. TREM2 expression was up-regulated in cortex of TBI mice model and in microglia stretching model, which was attenuated by DFO. After the mice were subjected to CCI, DFO treatment significantly up-regulated the protein levels of autophagy compared with the TBI group at 3days and caused an increase of autophagic vacuoles. Treatment with DFO reduced TBI-induced cell apoptosis, cerebral edema, neuroinflammation, and motor function impairment in mice, at least partly via the mTOR signaling pathway that facilitates the TREM2 activity. The results indicated that the maintenance of iron homeostasis by DFO plays neuroprotection by modulating the inflammatory response to TBI through TREM2-mediated autophagy. This study suggested that TREM2-mediated autophagy might be a potential target for therapeutic intervention in TBI.

Roles of microRNA-124 in traumatic brain injury: a comprehensive review.

Traumatic brain injury (TBI) is a prominent global cause of mortality due to the limited availability of effective prevention and treatment strategies for this disorder. An effective molecular biomarker may contribute to determining the prognosis and promoting the therapeutic efficiency of TBI. MicroRNA-124 (miR-124) is most abundantly expressed in the brain and exerts different biological effects in a variety of diseases by regulating pathological processes of apoptosis and proliferation. Recently, increasing evidence has demonstrated the association between miR-124 and TBI, but there is still a lack of relevant literature to summarize the current evidence on this topic. Based on this review, we found that miR-124 was involved as a regulatory factor in cell apoptosis and proliferation, and was also strongly related with the pathophysiological development of TBI. MiR-124 played an essential role in TBI by interacting with multiple biomolecules and signaling pathways, such as JNK, VAMP-3, Rela/ApoE, PDE4B/mTOR, MDK/TLR4/NF-κB, DAPK1/NR2B, JAK/STAT3, PI3K/AKT, Ras/MEK/Erk. The potential benefits of upregulating miR-124 in facilitating TBI recovery have been identified. The advancement of miRNA nanocarrier system technology presents an opportunity for miR-124 to emerge as a novel therapeutic target for TBI. However, the specific mechanisms underlying the role of miR-124 in TBI necessitate further investigation. Additionally, comprehensive large-scale studies are required to evaluate the clinical significance of miR-124 as a therapeutic target for TBI.

Vγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ−/− mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-β that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI.

A finite rotation, small strain 2D elastic head model, with applications in mild traumatic brain injury

Rotational head motions have been shown to play a key role in traumatic brain injury. There is great interest in developing methods to rapidly predict brain tissue strains and strain rates resulting from rotational head motions to estimate brain injury risk and to guide the design of protective equipment. Idealized continuum mechanics based head models provide an attractive approach for rapidly estimating brain strains and strain rates. These models are capable of capturing the wave dynamics and transient response of the brain while being significantly easier and faster to apply compared to more sophisticated and detailed finite element head models. In this work, we present a new idealized continuum mechanics based head model that accounts for the head’s finite rotations, which is an improvement upon prior models that have been based on a small rotation assumption. Despite the simplicity of the model, we show that the proposed 2D elastic finite rotations head model predicts comparable strains to a more detailed finite element head model, demonstrating the potential usefulness of the model in rapidly estimating brain injury risk. This newly proposed model can serve as a basis for introducing finite rotations into more sophisticated head models in the future.

Enhancement of the liver’s neuroprotective role ameliorates traumatic brain injury pathology

Traumatic brain injury (TBI) is a pervasive problem worldwide for which no effective treatment is currently available. Although most studies have focused on the pathology of the injured brain, we have noted that the liver plays an important role in TBI. Using two mouse models of TBI, we found that the enzymatic activity of hepatic soluble epoxide hydrolase (sEH) was rapidly decreased and then returned to normal levels following TBI, whereas such changes were not observed in the kidney, heart, spleen, or lung. Interestingly, genetic downregulation of hepatic Ephx2 (which encodes sEH) ameliorates TBI-induced neurological deficits and promotes neurological function recovery, whereas overexpression of hepatic sEH exacerbates TBI-associated neurological impairments. Furthermore, hepatic sEH ablation was found to promote the generation of A2 phenotype astrocytes and facilitate the production of various neuroprotective factors associated with astrocytes following TBI. We also observed an inverted V-shaped alteration in the plasma levels of four EET (epoxyeicosatrienoic acid) isoforms (5,6-, 8,9-,11,12-, and 14,15-EET) following TBI which were negatively correlated with hepatic sEH activity. However, hepatic sEH manipulation bidirectionally regulates the plasma levels of 14,15-EET, which rapidly crosses the blood-brain barrier. Additionally, we found that the application of 14,15-EET mimicked the neuroprotective effect of hepatic sEH ablation, while 14,15-epoxyeicosa-5(Z)-enoic acid blocked this effect, indicating that the increased plasma levels of 14,15-EET mediated the neuroprotective effect observed after hepatic sEH ablation. These results highlight the neuroprotective role of the liver in TBI and suggest that targeting hepatic EET signaling could represent a promising therapeutic strategy for treating TBI.

USP11 exacerbates neuronal apoptosis after traumatic brain injury via PKM2-mediated PI3K/AKT signaling pathway.

Ubiquitin-specific protease 11 (USP11) is a ubiquitin-specific protease involved in the regulation of protein ubiquitination. However, its role in traumatic brain injury (TBI) remains unclear. This experiment suggests that USP11 is possibly involved in regulating neuronal apoptosis in TBI. Therefore, we use precision impactor device to established a TBI rat model and assayed the role of USP11 by overexpressing and inhibiting USP11. We found that Usp11 expression increased after TBI. In addition, we hypothesized that pyruvate kinase M2 (PKM2) is a potential USP11 target and experimentally confirmed that upregulation of Usp11 increased Pkm2 expression. Furthermore, elevated USP11 levels exacerbate blood-brain barrier damage, brain edema, and neurobehavioral impairment and cause apoptosis induction through Pkm2 upregulation. Moreover, we hypothesize that PKM2-induced neuronal apoptosis is mediated by the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Our findings were confirmed by changes in Pi3k and Akt expression with Usp11 upregulation and downregulation and PKM2 inhibition. In conclusion, our findings show that USP11 exacerbates injury in TBI through PKM2 and causes neurological impairment and neuronal apoptosis through the PI3K/AKT signaling pathway.