Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

BACKGROUND: Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. PURPOSE: To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. STUDY TYPE: Prospective. POPULATION: Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). FIELD STRENGTH/SEQUENCE: 3-T, single-shot echo-planar imaging sequence. ASSESSMENT: Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). STATISTICAL TESTS: Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. RESULTS: mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (ß = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (ß = 5.67, 95% CI 4.56, 6.97), executive function (ß = 2.34, 95% CI 1.49, 3.20), and PSMD (ß = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. DATA CONCLUSION: Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Classification, risk factors, and outcomes of patients with progressive hemorrhagic injury after traumatic brain injury.

BACKGROUND: According to the pathoanatomic classification system, progressive hemorrhagic injury (PHI) can be categorized into progressive intraparenchymal contusion or hematoma (pIPCH), epidural hematoma (pEDH), subdural hematoma (pSDH), and traumatic subarachnoid hemorrhage (ptSAH). The clinical features of each type differ greatly. The objective of this study was to determine the predictors, clinical management, and outcomes of PHI according to this classification. METHODS: Multivariate logistic regression analysis was used to identify independent risk factors for PHI and each subgroup. Patients with IPCH or EDH were selected for subgroup propensity score matching (PSM) to exclude confounding factors before evaluating the association of hematoma progression with the outcomes by classification. RESULTS: In the present cohort of 419 patients, 123 (29.4%) demonstrated PHI by serial CT scan. Of them, progressive ICPH (58.5%) was the most common type, followed by pEDH (28.5%), pSDH (9.8%), and ptSAH (3.2%). Old age (≥ 60 years), lower motor Glasgow Coma Scale score, larger primary lesion volume, and higher level of D-dimer were independent risk factors related to PHI. These factors were also independent predictors for pIPCH, but not for pEDH. The time to first CT scan and presence of skull linear fracture were robust risk factors for pEDH. After PSM, the 6-month mortality and unfavorable survival rates were significantly higher in the pIPCH group than the non-pIPCH group (24.2% vs. 1.8% and 12.1% vs. 7.3%, respectively, p < 0.001), but not significantly different between the pEDH group and the non-pEDH group. CONCLUSIONS: Understanding the specific patterns of PHI according to its classification can help early recognition and suggest targeted prevention or treatment strategies to improve patients' neurological outcomes.

ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFκB/NLRP3 pathway.

BACKGROUND: Microglia-mediated neuroinflammatory response following traumatic brain injury (TBI) is considered as a vital secondary injury factor, which drives trauma-induced neurodegeneration and is lack of efficient treatment. ACT001, a sesquiterpene lactone derivative, is reportedly involved in alleviation of inflammatory response. However, little is known regarding its function in regulating innate immune response of central nervous system (CNS) after TBI. This study aimed to investigate the role and underlying mechanism of ACT001 in TBI. METHODS: Controlled cortical impact (CCI) models were used to establish model of TBI. Cresyl violet staining, evans blue extravasation, neurobehavioral function assessments, immunofluorescence and transmission electron microscopy were used to evaluate therapeutic effects of ACT001 in vivo. Microglial depletion was induced by administering mice with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Cell-cell interaction models were established as co-culture system to simulate TBI conditions in vitro. Cytotoxic effect of ACT001 on cell viability was assessed by cell counting kit-8 and activation of microglia cells were induced by Lipopolysaccharides (LPS). Pro-inflammatory cytokines expression was determined by Real-time PCR and nitric oxide production. Apoptotic cells were detected by TUNEL and flow cytometry assays. Tube formation was performed to evaluate cellular angiogenic ability. ELISA and western blot experiments were used to determine proteins expression. Pull-down assay was used to analyze proteins that bound ACT001. RESULTS: ACT001 relieved the extent of blood-brain barrier integrity damage and alleviated motor function deficits after TBI via reducing trauma-induced activation of microglia cells. Delayed depletion of microglia with PLX5622 hindered therapeutic effect of ACT001. Furthermore, ACT001 alleviated LPS-induced activation in mouse and rat primary microglia cells. Besides, ACT001 was effective in suppressing LPS-induced pro-inflammatory cytokines production in BV2 cells, resulting in reduction of neuronal apoptosis in HT22 cells and improvement of tube formation in bEnd.3 cells. Mechanism by which ACT001 functioned was related to AKT/NFκB/NLRP3 pathway. ACT001 restrained NFκB nuclear translocation in microglia cells through inhibiting AKT phosphorylation, resulting in decrease of NLRP3 inflammasome activation, and finally down-regulated microglial neuroinflammatory response. CONCLUSIONS: Our study indicated that ACT001 played critical role in microglia-mediated neuroinflammatory response and might be a novel potential chemotherapeutic drug for TBI. Video Abstract.

Chordoid Glioma: A Neoplasm Found in the Anterior Part of the Third Ventricle.

ABSTRACT: Chordoid glioma is a rare low-grade tumor that originates almost exclusively in the anterior part of the third ventricle. The diagnosis and treatment of the tumor remain controversial. In this article, the authors present a novel case of chordoid glioma of the third ventricle. The patient was treated with less invasive microsurgery followed by low-dose gamma knife radiosurgery. Magnetic resonance imaging revealed a decrease in tumor size and necrosis in the central region of the tumor, without significant complications at follow-up 14 months later. Based on these findings, the authors suggest that less invasive microsurgical resection followed by low-dose gamma knife radiosurgery is safe and effective for the treatment of chordoid glioma of the third ventricle.

Hydrogen postconditioning promotes survival of rat retinal ganglion cells against ischemia/reperfusion injury through the PI3K/Akt pathway.

Retinal ischemia/reperfusion injury (IRI) plays a crucial role in the pathophysiology of various ocular diseases. Our previous study have shown that postconditioning with inhaled hydrogen (H2) (HPC) can protect retinal ganglion cells (RGCs) in a rat model of retinal IRI. Our further study aims to investigate potential mechanisms underlying HPC-induced protection. Retinal IRI was performed on the right eyes of rats and was followed by inhalation of 67% H2 mixed with 33% oxygen immediately after ischemia for 1 h daily for one week. RGC density was counted using haematoxylin and eosin (HE) staining, retrograde labelling with cholera toxin beta (CTB) and TUNEL staining, respectively. Visual function was assessed using flash visual evoked potentials (FVEP) and pupillary light reflex (PLR). The phosphorylated Akt was analysed by RT-PCR and western blot. The results showed that administration of HPC significantly inhibited the apoptosis of RGCs and protected the visual function. Simultaneously, HPC treatment markedly increased the phosphorylations of Akt. Blockade of PI3K activity by inhibitors (LY294002) dramatically abolished its anti-apoptotic effect and lowered both visual function and Akt phosphorylation levels. Taken together, our results demonstrate that HPC appears to confer neuroprotection against retinal IRI via the PI3K/Akt pathway.

Sesamin protects SH-SY5Y cells against mechanical stretch injury and promoting cell survival.

BACKGROUND: Sesamin is a well-known antioxidant extracted from sesame seeds that exhibits various curative effects. The present study investigated whether sesamin would protect neuroblastoma SH-SY5Y cells against mechanical stretch injury-induced increases in reactive oxygen species (ROS) and apoptosis. Additionally, the mechanisms underlying these actives were investigated. Following exposure to mechanical stretch injury, cells were incubated for further investigations. Lactate dehydrogenase and Cell Counting Kit-8 assays were used to assess cell viability, and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometric analysis were performed to evaluate changes in mitochondrial membrane potential (ΔΨm). Furthermore, intracellular levels of ROS production were measured by 20, 70-dichlorofluorescein diacetate staining, the mRNA levels of matrix metallopeptidase 9 (MMP-9) were evaluated using real-time polymerase chain reaction analysis, and the determinations had also been made on related proteins by Western blot analysis. RESULTS: Exposure to mechanical stretch injury significantly decreased cell viability but this decrease was attenuated by pretreatment with sesamin (50 µM). Sesamin also significantly inhibited mechanical stretch injury-induced increases in intracellular ROS production, attenuated declines in ΔΨm, diminished the expressions of pro-apoptotic proteins, and decreased cell apoptosis. Stretch injury increased Bax and cleaved caspase 3 levels, enhanced the gene expression of MMP-9, increased the phosphorylation levels of Akt, p38, and JNK and decreased Bcl-2 levels in the cells. However, pretreatment with sesamin reduced the mechanical stretch injury-induced overexpression of MMP-9. CONCLUSIONS: Sesamin protected SH-SY5Y cells against stretch injury by attenuating increases in ROS levels and suppressing apoptosis. Accordingly, sesamin seems to be a potentially therapeutic agent in the treatment of traumatic brain injury.

Sesamin alleviates blood-brain barrier disruption in mice with experimental traumatic brain injury.

Sesamin, a major lignan of sesame oil, was reported to have neuroprotective effects in several brain injury models. However, its protective action in maintaining blood-brain barrier (BBB) integrity has not been studied. In this study we investigated the effects of sesamin on the BBB in a mouse model of traumatic brain injury (TBI) and explored the underlying mechanisms. Adult male C57BL/6 mice were subjected to a controlled cortical impact (CCI) injury and then received sesamin (30 mg·kg-1·d-1, ip). The mice were euthanized on the 1st and 3rd days after CCI injury and samples were collected for analysis. Sesamin treatment significantly attenuated CCI-induced brain edema on the 1st and 3rd days after the injury, evidenced by the decreases in water content, tissue hemoglobin levels, Evans blue extravasation and AQP4 expression levels in the ipsilateral cortical tissue compared with the vehicle-treated group. Furthermore, sesamin treatment significantly alleviated CCI-induced loss of the tight junction proteins ZO-1 and occludin in the brain tissues. The neuroprotective mechanisms of sesamin were further explored in cultured mouse brain microvascular bEnd.3 cells subjected to biaxial stretch injury (SI). Pretreatment with sesamin (50 µmol/L) significantly alleviated SI-induced loss of ZO-1 in bEnd.3 cells. Furthermore, we revealed that pretreatment with sesamin significantly attenuated SI-induced oxidative stress and early-stage apoptosis in bEnd.3 cells by decreasing the activation of ERK, p-38 and caspase-3. In conclusion, sesamin alleviates BBB disruption at least partly through its anti-oxidative and anti-apoptotic effects on endothelial cells in CCI injury. These findings suggest that sesamin may be a promising potential therapeutic intervention for preventing disruption of the BBB after TBI.

Risk factors for recurrence of chronic subdural hematoma after burr hole surgery: potential protective role of dexamethasone.

OBJECTIVE: Chronic subdural hematomas (CSDHs) are often found in neurosurgery, and display a recurrence rate of up to 37%. This study aimed to determine potential risk factors contributing to unilateral CSDH recurrence, and evaluate the role of postoperative management with dexamethasone (DX) in reducing recurrence. METHODS: Between January 2010 and May 2015, a total of 242 consecutive patients with CSDH treated with burr-hole trephination were included in this study. Univariate and multivariate analyses were performed to determine risk factors potentially associated with the recurrence of CSDH. Then, patients at high risk were divided into DX and non-DX treatment groups, respectively. Chi-square test was used to assess the potential role of DX. RESULTS: CSDH recurrence was recorded in 39 patients (16.1%). Among various risk factors, advanced age (p = .01), preoperative midline displacement exceeding 10 mm (p < .001), and hematomas presenting with separated type (p = .03) were significantly associated with CSDH recurrence. Interestingly, patients who accepted therapy with DX had a lower rate of second drainage procedure (p = .017). In addition, DX effectively reduced disease recurrence in patients with the separated type of hematoma (p = .047), and seemed to be beneficial to those with advanced age and midline shift exceeding 10 mm, although statistical significance was not achieved. CONCLUSION: These findings indicated that advanced age, midline displacement, and mixed density hematoma are independent factors for unilateral CSDH recurrence. When the above factors are detected in patients, additional DX administration should be recommended after operation.

Transplantation of astrocyte-derived mitochondria into injured astrocytes has a protective effect following stretch injury.

Traumatic brain injury (TBI) is a global public-health problem. Astrocytes, and their mitochondria, are important factors in the pathogenesis of TBI-induced secondary injury. Mitochondria extracted from healthy tissues and then transplanted have shown promise in models of a variety of diseases. However, the effect on recipient astrocytes is unclear. Here, we isolated primary astrocytes from newborn C57BL/6 mice, one portion of which was used to isolate mitochondria, and another was subjected to stretch injury (SI) followed by transplantation of the isolated mitochondria. After incubation for 12 h, cell viability, mitochondrial dysfunction, calcium overload, redox stress, inflammatory response, and apoptosis were improved. Live-cell imaging showed that the transplanted mitochondria were incorporated into injured astrocytes and fused with their mitochondrial networks, which was in accordance with the changes in the expression levels of markers of mitochondrial dynamics. The astrocytic IKK/NF-κB pathway was decelerated whereas the AMPK/PGC-1α pathway was accelerated by transplantation. Together, these results indicate that exogenous mitochondria from untreated astrocytes can be incorporated into injured astrocytes and fuse with their mitochondrial networks, improving cell viability by ameliorating mitochondrial dysfunction, redox stress, calcium overload, and inflammation.

Endorepellin downregulation promotes angiogenesis after experimental traumatic brain injury.

Endorepellin plays a key role in the regulation of angiogenesis, but its effects on angiogenesis after traumatic brain injury are unclear. This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice. Mice were randomly divided into four groups: sham, controlled cortical impact only, adeno-associated virus (AAV)-green fluorescent protein, and AAV-shEndorepellin-green fluorescent protein groups. In the controlled cortical impact model, the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+ proliferating endothelial cells and the functional microvessel density in mouse brain. These changes resulted in improved neurological function compared with controlled cortical impact mice. Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein. Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization, which may further improve neurobehavioral outcomes. Furthermore, an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control. Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor- and angiopoietin-1-related signaling pathways.

PIEZO1-Related Physiological and Pathological Processes in CNS: Focus on the Gliomas.

PIEZO1 is ubiquitously expressed in cells in different kinds of tissues throughout the body, which can sense physical or mechanical stimuli and translate them into intracellular electrochemical signals to regulate organism functions. In particular, PIEZO1 appears in complex interactive regulatory networks as a central node, governing normal and pathological functions in the body. However, the effect and mechanism of the activation or expression of PIEZO1 in diseases of the central nervous system (CNS) remain unclear. On one hand, in CNS diseases, pathophysiological processes in neurons and glial are often accompanied by variations in the mechanical properties of the cellular and extracellular matrix stiffness. The expression of PIEZO1 can therefore be upregulated, in responding to mechanical stimulation, to drive the biological process in cells, which in turns indirectly affects the cellular microenvironment, resulting in alterations of the cellular status. On the other hand, it may have contradictory effects with the change of active patterns and/or subcellular location. This review highlights the biological processes involved with PIEZO1 in CNS cells, with special emphasis on its multiple roles in glioma-associated phenotypes. In conclusion, PIEZO1 can be used as an indicator to assess the malignancy and prognosis of patients with gliomas, as well as a therapeutic target for clinical application following fully exploring the potential mechanism of PIEZO1 in CNS diseases.

The role and potential therapeutic targets of astrocytes in central nervous system demyelinating diseases.

Astrocytes play vital roles in the central nervous system, contributing significantly to both its normal functioning and pathological conditions. While their involvement in various diseases is increasingly recognized, their exact role in demyelinating lesions remains uncertain. Astrocytes have the potential to influence demyelination positively or negatively. They can produce and release inflammatory molecules that modulate the activation and movement of other immune cells. Moreover, they can aid in the clearance of myelin debris through phagocytosis and facilitate the recruitment and differentiation of oligodendrocyte precursor cells, thereby promoting axonal remyelination. However, excessive or prolonged astrocyte phagocytosis can exacerbate demyelination and lead to neurological impairments. This review provides an overview of the involvement of astrocytes in various demyelinating diseases, emphasizing the underlying mechanisms that contribute to demyelination. Additionally, we discuss the interactions between oligodendrocytes, oligodendrocyte precursor cells and astrocytes as therapeutic options to support myelin regeneration. Furthermore, we explore the role of astrocytes in repairing synaptic dysfunction, which is also a crucial pathological process in these disorders.

Knockout of Sirt2 alleviates traumatic brain injury in mice.

Sirtuin 2 (SIRT2) inhibition or Sirt2 knockout in animal models protects against the development of neurodegenerative diseases and cerebral ischemia. However, the role of SIRT2 in traumatic brain injury (TBI) remains unclear. In this study, we found that knockout of Sirt2 in a mouse model of TBI reduced brain edema, attenuated disruption of the blood-brain barrier, decreased expression of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, reduced the activity of the effector caspase-1, reduced neuroinflammation and neuronal pyroptosis, and improved neurological function. Knockout of Sirt2 in a mechanical stretch injury cell model in vitro also decreased expression of the NLRP3 inflammasome and pyroptosis. Our findings suggest that knockout of Sirt2 is neuroprotective against TBI; therefore, Sirt2 could be a novel target for TBI treatment.

Inhibiting phosphatase and actin regulator 1 expression is neuroprotective in the context of traumatic brain injury.

Studies have found that the phosphatase actin regulatory factor 1 expression can be related to stroke, but it remains unclear whether changes in phosphatase actin regulatory factor 1 expression also play a role in traumatic brain injury. In this study we found that, in a mouse model of traumatic brain injury induced by controlled cortical impact, phosphatase actin regulatory factor 1 expression is increased in endothelial cells, neurons, astrocytes, and microglia. When we overexpressed phosphatase actin regulatory factor 1 by injection an adeno-associated virus vector into the contused area in the traumatic brain injury mice, the water content of the brain tissue increased. However, when phosphatase actin regulatory factor 1 was knocked down, the water content decreased. We also found that inhibiting phosphatase actin regulatory factor 1 expression regulated the nuclear factor kappa B signaling pathway, decreased blood-brain barrier permeability, reduced aquaporin 4 and intercellular adhesion molecule 1 expression, inhibited neuroinflammation, and neuronal apoptosis, thereby improving neurological function. The findings from this study indicate that phosphatase actin regulatory factor 1 may be a potential therapeutic target for traumatic brain injury.

MRI-Visible Perivascular Spaces Associated With Cognitive Impairment in Military Veterans With Traumatic Brain Injury Mediated by CSF P-Tau.

Objective: To investigate the association of MRI-visible perivascular spaces (PVS) with cognitive impairment in military veterans with traumatic brain injury (TBI), and whether cerebrospinal fluid (CSF) p-tau and Aß mediate this effect. Materials and Methods: We included 55 Vietnam War veterans with a history of TBI and 52 non-TBI Vietnam War veterans from the Department of Defense Alzheimer's Disease Neuroimaging Initiative (ADNI) database. All the subjects had brain MRI, CSF p-tau, Aß, and neuropsychological examinations. MRI-visible PVS number and grade were rated on MRI in the centrum semiovale (CSO-PVS) and basal ganglia (BG-PVS). Multiple linear regression was performed to assess the association between MRI-visible PVS and cognitive impairment and the interaction effect of TBI. Additionally, mediation effect of CSF biomarkers on the relationship between MRI-visible PVS and cognitive impairment was explored in TBI group. Results: Compared with military control, TBI group had higher CSO-PVS number (p = 0.001), CSF p-tau (p = 0.022) and poorer performance in verbal memory (p = 0.022). High CSO-PVS number was associated with poor verbal memory in TBI group (ß = -0.039, 95% CI -0.062, -0.016), but not in military control group (ß = 0.019, 95% CI -0.004, 0.043) (p-interaction = 0.003). Further mediation analysis revealed that CSF p-tau had a significant indirect effect (ß = -0.009, 95% CI: -0.022 -0.001, p = 0.001) and mediated 18.75% effect for the relationship between CSO-PVS and verbal memory in TBI group. Conclusion: MRI-visible CSO-PVS was more common in Vietnam War veterans with a history of TBI and was associated with poor verbal memory, mediated partially by CSF p-tau.

Cell cycle exit and neuronal differentiation 1-engineered embryonic neural stem cells enhance neuronal differentiation and neurobehavioral recovery after experimental traumatic brain injury.

Our previous study showed that cell cycle exit and neuronal differentiation 1 (CEND1) may participate in neural stem cell cycle exit and oriented differentiation. However, whether CEND1-transfected neural stem cells can improve the prognosis of traumatic brain injury remained unclear. In this study, we performed quantitative proteomic analysis and found that after traumatic brain injury, CEND1 expression was downregulated in mouse brain tissue. Three days after traumatic brain injury, we transplanted CEND1-transfected neural stem cells into the area surrounding the injury site. We found that at 5 weeks after traumatic brain injury, transplantation of CEND1-transfected neural stem cells markedly alleviated brain atrophy and greatly improved neurological function. In vivo and in vitro results indicate that CEND1 overexpression inhibited the proliferation of neural stem cells, but significantly promoted their neuronal differentiation. Additionally, CEND1 overexpression reduced protein levels of Notch1 and cyclin D1, but increased levels of p21 in CEND1-transfected neural stem cells. Treatment with CEND1-transfected neural stem cells was superior to similar treatment without CEND1 transfection. These findings suggest that transplantation of CEND1-transfected neural stem cells is a promising cell therapy for traumatic brain injury. This study was approved by the Animal Ethics Committee of the School of Biomedical Engineering of Shanghai Jiao Tong University, China (approval No. 2016034) on November 25, 2016.

Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice.

Urolithin A (UA) is a natural metabolite produced from polyphenolics in foods such as pomegranates, berries, and nuts. UA is neuroprotective against Parkinson's disease, Alzheimer's disease, and cerebral hemorrhage. However, its effect against traumatic brain injury remains unknown. In this study, we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA. We found that UA greatly reduced brain edema; increased the expression of tight junction proteins in injured cortex; increased the immunopositivity of two neuronal autophagy markers, microtubule-associated protein 1A/B light chain 3A/B (LC3) and p62; downregulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), two regulators of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway; decreased the phosphorylation levels of inhibitor of NFκB (IκB) kinase alpha (IKKα) and nuclear factor kappa B (NFκB), two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway; reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex; and improved mouse neurological function. These findings suggest that UA may be a candidate drug for the treatment of traumatic brain injury, and its neuroprotective effects may be mediated by inhibition of the PI3K/Akt/mTOR and Akt/IKK/NFκB signaling pathways, thus reducing neuroinflammation and enhancing autophagy.

Upregulation of C Terminus of Hsc70-Interacting Protein Attenuates Apoptosis and Procoagulant Activity and Facilitates Brain Repair After Traumatic Brain Injury.

Traumatic brain injury (TBI) could highly induce coagulopathy through breaking the dynamic balance between coagulation and fibrinolysis systems, which may be a major contributor to the progressive secondary injury cascade that occurs after TBI. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition is reported to exert neuroprotection in TBI, making it a potential regulatory target involved in TBI-induced coagulation disorder. PTEN level is controlled in a major way by E3 ligase-mediated degradation through the ubiquitin-proteasome system. The C terminus of Hsc70-interacting protein (CHIP) has been shown to regulate proteasomal degradation and ubiquitination level of PTEN. In the present study, CHIP was overexpressed and knocked down in mouse brain microvascular endothelial cells (bEnd.3) and tissues during the early phase of TBI. In vitro cell proliferation, cell apoptosis, migration capacity, and invasion capacity were determined. The changes of procoagulant and apoptosis molecules after TBI were also detected as well as the micrangium density and blood-brain barrier permeability after in vivo TBI. In vitro results demonstrated that CHIP overexpression facilitated bEnd.3 cell proliferation, migration, and invasion and downregulated cell apoptosis and the expressions of procoagulant molecules through promoting PTEN ubiquitination in a simulated TBI model with stretch-induced injury treatment. In vivo experiments also demonstrated that CHIP overexpression suppressed post-TBI apoptosis and procoagulant protein expressions, as well as increased microvessel density, reduced hemorrhagic injury, and blood-brain barrier permeability. These findings suggested that the upregulation of CHIP may attenuate apoptosis and procoagulant activity, facilitate brain repair, and thus exerts neuroprotective effects in TBI.

Aloin Protects Against Blood-Brain Barrier Damage After Traumatic Brain Injury in Mice.

Aloin is a small-molecule drug well known for its protective actions in various models of damage. Traumatic brain injury (TBI)-induced cerebral edema from secondary damage caused by disruption of the blood-brain barrier (BBB) often leads to an adverse prognosis. Since the role of aloin in maintaining the integrity of the BBB after TBI remains unclear, we explored the protective effects of aloin on the BBB using in vivo and in vitro TBI models. Adult male C57BL/6 mice underwent controlled cortical impact injury, and mouse brain capillary endothelial bEnd.3 cells underwent biaxial stretch injury, then both received aloin treatment. In the animal experiments, we found 20 mg/kg aloin to be the optimum concentration to decrease cerebral edema, decrease disruption of the BBB, and improve neurobehavioral performance after cortical impact injury. In the cellular studies, the optimum concentration of 40 µg/mL aloin reduced apoptosis and reversed the loss of tight junctions by reducing the reactive oxygen species levels and changes in mitochondrial membrane potential after stretch injury. The mechanisms may be that aloin downregulates the phosphorylation of p38 mitogen-activated protein kinase, the activation of p65 nuclear factor-kappa B, and the ratios of B cell lymphoma (Bcl)-2-associated X protein/Bcl-2 and cleaved caspase-3/caspase-3. We conclude that aloin exhibits these protective effects on the BBB after TBI through its anti-oxidative stress and anti-apoptotic properties in mouse brain capillary endothelial cells. Aloin may thus be a promising therapeutic drug for TBI.

Early stage of diffusional kurtosis imaging and dynamic contrast-enhanced magnetic resonance imaging correlated with long-term neurocognitive function after experimental traumatic brain injury.

Development of a reliable biomarker for prognostic monitoring of cognitive impairment after traumatic brain injury (TBI) is of great importance. The aim of the study was to explore the value of early diffusional kurtosis imaging (DKI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in evaluation of chronic cognitive function after TBI. MRI was performed on TBI and control rats at 7 days post-injury. MRI parameters were measured in bilateral cortex, hippocampus, thalamus and corpus callosum (CC). All the rats underwent Morris water maze (MWM) at 6 months after injury. Immunohistochemistry (IHC) analysis of neuron [NeuN], astroglia [GFAP], microglia [Iba-1], and myelin [MBP] was performed after the MWM test. Our study revealed that, TBI group showed higher volume transfer coefficient (Ktrans) value in ipsilateral cortex (P < 0.0001) and no detectable changes in other regions-of-interest (ROIs), compared with control group. DKI showed higher MK in all ipsilateral ROIs (P < 0.05), higher MD in ipsilateral cortex, hippocampus and CC (P < 0.05 for all) in TBI group. TBI group had worse performance in MWM test at 6 months post-injury(P < 0.05). IHC analysis showed lower NeuN, and higher GFAP and Iba-1 in all ipsilateral ROIs (P < 0.05) in TBI rats. NeuN, and GFAP and Iba-1 correlated significantly with MK value in ipsilateral regions of cortex. The MK value of ipsilateral cortex and CC and Ktrans value of ipsilateral cortex also correlated significantly with time in the target quadrant. Therefore, our study indicated that early DKI and DCE-MRI could be used to assess the microstructural changes associated with long-term cognitive outcome following TBI.