Modeling Traumatic Brain Injury In Vitro

Abstract Background Every year, millions of people suffer from various forms of traumatic brain injury (TBI), and new approaches with therapeutic potential are required. Although chemokines are known to be involved in brain injury, the importance of X-C motif chemokine ligand 1 (XCL1) and its receptors, X-C motif chemokine receptor 1 (XCR1) and alpha-9 integrin (ITGA9), in the progression of TBI remain unknown. Methods Using RT-qPCR/Western blot/ELISA techniques, changes in the mRNA/protein levels of XCL1 and its two receptors, in brain areas at different time points were measured in a mouse model of TBI. Moreover, their cellular origin and possible changes in expression were evaluated in primary glial cell cultures. Results Studies revealed the spatiotemporal upregulation of the mRNA expression of XCL1, XCR1 and ITGA9 in all the examined brain areas (cortex, thalamus, and hippocampus) and at most of the evaluated stages after brain injury (24 h; 4, 7 days; 2, 5 weeks), except for ITGA9 in the thalamus. Moreover, changes in XCL1 protein levels occurred in all the studied brain structures; the strongest upregulation was observed 24 h after trauma. Our in vitro experiments proved that primary murine microglial and astroglial cells expressed XCR1 and ITGA9, however they seemed not to be a main source of XCL1. Conclusions These findings indicate that the XCL1/XCR1 and XCL1/ITGA9 axes may participate in the development of TBI. The XCL1 can be considered as one of the triggers of secondary injury, therefore XCR1 and ITGA9 may be important targets for pharmacological intervention after traumatic brain injury. Graphic abstract

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The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway

International Journal of Molecular Medicine ◽

10.3892/ijmm.2011.870 ◽

2011 ◽

Vol 29 (4) ◽

pp. 630-636 ◽

Cited By ~ 32

Author(s):

TAO CHEN ◽

LEI ZHANG ◽

YAN QU ◽

KAI HUO ◽

XIAOFAN JIANG ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Akt Pathway

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Embedded axonal fiber tracts improve finite element model predictions of traumatic brain injury

Biomechanics and Modeling in Mechanobiology ◽

10.1007/s10237-019-01273-8 ◽

2019 ◽

Vol 19 (3) ◽

pp. 1109-1130 ◽

Cited By ~ 3

Author(s):

Marzieh Hajiaghamemar ◽

Taotao Wu ◽

Matthew B. Panzer ◽

Susan S. Margulies

Keyword(s):

Traumatic Brain Injury ◽

Finite Element ◽

Brain Injury ◽

Strain Rate ◽

Brain Tissue ◽

Brain Injuries ◽

Characteristic Curve ◽

Strain And Strain Rate

AbstractWith the growing rate of traumatic brain injury (TBI), there is an increasing interest in validated tools to predict and prevent brain injuries. Finite element models (FEM) are valuable tools to estimate tissue responses, predict probability of TBI, and guide the development of safety equipment. In this study, we developed and validated an anisotropic pig brain multi-scale FEM by explicitly embedding the axonal tract structures and utilized the model to simulate experimental TBI in piglets undergoing dynamic head rotations. Binary logistic regression, survival analysis with Weibull distribution, and receiver operating characteristic curve analysis, coupled with repeated k-fold cross-validation technique, were used to examine 12 FEM-derived metrics related to axonal/brain tissue strain and strain rate for predicting the presence or absence of traumatic axonal injury (TAI). All 12 metrics performed well in predicting of TAI with prediction accuracy rate of 73–90%. The axonal-based metrics outperformed their rival brain tissue-based metrics in predicting TAI. The best predictors of TAI were maximum axonal strain times strain rate (MASxSR) and its corresponding optimal fraction-based metric (AF-MASxSR7.5) that represents the fraction of axonal fibers exceeding MASxSR of 7.5 s−1. The thresholds compare favorably with tissue tolerances found in in–vitro/in–vivo measurements in the literature. In addition, the damaged volume fractions (DVF) predicted using the axonal-based metrics, especially MASxSR (DVF = 0.05–4.5%), were closer to the actual DVF obtained from histopathology (AIV = 0.02–1.65%) in comparison with the DVF predicted using the brain-related metrics (DVF = 0.11–41.2%). The methods and the results from this study can be used to improve model prediction of TBI in humans.

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Nerve Level Traumatic Brain Injury in in Vivo/in Vitro Experiments

10.4271/2010-22-0010 ◽

2010 ◽

Cited By ~ 1

Author(s):

Yasuhiro Matsui ◽

Tetsuya Nishimoto

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

In Vitro Experiments

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Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model

Human & Experimental Toxicology ◽

10.1177/0960327113509659 ◽

2013 ◽

Vol 33 (7) ◽

pp. 673-684 ◽

Cited By ~ 35

Author(s):

D Torrente ◽

MF Avila ◽

R Cabezas ◽

L Morales ◽

J Gonzalez ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Brain Injury ◽

Wound Closure ◽

Human Mesenchymal Stem Cells ◽

Neuronal Population ◽

Paracrine Factors ◽

Neuroprotective Strategy

Traumatic brain injury (TBI) consists of a primary and a secondary insult characterized by a biochemical cascade that plays a crucial role in cell death in the brain. Despite the major improvements in the acute care of head injury victims, no effective strategies exist for preventing the secondary injury cascade. This lack of success might be due to that most treatments are aimed at targeting neuronal population, even if studies show that astrocytes play a key role after a brain damage. In this work, we propose a new model of in vitro traumatic brain-like injury and use paracrine factors released by human mesenchymal stem cells (hMSCs) as a neuroprotective strategy. Our results demonstrate that hMSC-conditioned medium increased wound closure and proliferation at 12 h and reduced superoxide production to control conditions. This was accompanied by changes in cell morphology and polarity index, as both parameters reflect the ability of cells to migrate toward the wound. These findings indicate that hMSC is an important regulator of oxidative stress production, enhances cells migration, and shall be considered as a useful neuroprotective approach for brain recovery following injury.

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miR-29a-5p Alleviates Traumatic Brain Injury- (TBI-) Induced Permeability Disruption via Regulating NLRP3 Pathway

Disease Markers ◽

10.1155/2021/9556513 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Aijun Zhang ◽

Youming Lu ◽

Lei Yuan ◽

Pengqi Zhang ◽

Dongdong Zou ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Endothelial Cells ◽

Brain Injury ◽

Water Content ◽

Nlrp3 Inflammasome ◽

Cell Permeability ◽

Luciferase Reporter ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

Objective. Inactivation of NLRP3 inflammasome plays a role in reducing the permeability of endothelial cells and improving blood-brain barrier (BBB) dysfunction following traumatic brain injury (TBI). However, the mechanism controlling NLRP3 inflammasome activation remains unclear. This study is aimed at defining the role of miR-29a-5p in NLRP3 inflammasome activation and permeability of endothelial cells under TBI. Methods. The scratch injury model on brain bEnd.3 microvascular endothelial cells was used as in vitro TBI model cells. Effects of miR-29a mimics and inhibitors on TBI model cells were observed by examining their action on FITC, TEER, and protein contents of ZO-1 and occludin, and cell permeability-associated protein. Luciferase reporter assay evaluated miR-29a-5p targeting to NLRP3. ELISA examined of IL-1β and IL-18 levels. miR-29a-5p mimic was injected into TBI mouse and its effect on BBB, indicated by Evans blue (EB) staining assay and cerebral water content, and NLRP3 activation was examined. Results. miR-29a-3p and miR-29a-5p mimics decrease the concentration of FITC, and increase TEER and the protein contents of ZO-1 and occludin in TBI model cells. miR-29a-5p silencing disrupted the permeability of mouse bEnd.3 cells. miR-29a-5p targets to NLRP3 through the binding on its 3 ′ UTR and negatively regulates its expression in TBI model cells. NLRP3 inhibition and miR-29a-5p silencing together caused significantly decreased FITC concentration and increased TEER value and release of IL-1β and IL-18. miR-29a-5p mimic alleviated the BBB and cerebral water content and inactivates NLRP3 in the mouse TBI model. Conclusions. miR-29a-5p mimics protect TBI-induced increased endothelial cell permeability and BBB dysfunction via suppressing NLRP3 expression and activation.

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FGF20 protected against BBB disruption after traumatic brain injury by activating the AKT/GSK3β pathway to upregulate junction protein expression and inhibiting JNK/NFκB-dependent neuroinflammation

10.21203/rs.2.19529/v1 ◽

2019 ◽

Author(s):

Jun Chen ◽

Xue Wang ◽

Jian Hu ◽

Wenting Huang ◽

Confidence Dordoe ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Brain Edema ◽

Microvascular Endothelial Cell ◽

Potential Candidate ◽

Protective Effects ◽

Tnf Α ◽

Junction Protein

Abstract Background ：Blood-brain barrier (BBB) disruption and the cerebral inflammatory response are two reciprocal mechanisms that work together to mediate the degree of brain edema, which is responsible for the majority of deaths after traumatic brain injury (TBI), and facilitate further brain damage, which leads to long-term TBI complications. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in the development of dopaminergic neurons in Parkinson disease (PD). However, little is known about the role of FGF20 in TBI. The aim of the current study was to assess the protective effects of FGF20 in TBI through protecting the BBB. Methods: We explored the relationship between FGF20 and BBB function in controlled cortical impact (CCI)-induced TBI mice model and TNF-α-induced human brain microvascular endothelial cell (HBMEC) in vitro BBB disruption model. We also explored the mechanisms of these interactions and the signaling processes involved in BBB function and neuroinflammation. Results: In this study, we demonstrate that recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema and Evans Blue penetration in vivo after TBI. In an in vitro BBB disruption model of, rhFGF20 could reverse changes to TNF-α-induced HBMEC morphology, reduce Transwell permeability, and increase transendothelial electrical resistance (TEER). In both a TBI mouse model and in vitro , rhFGF20 upregulated the expression of BBB-associated tight junction (TJ) protein and adherens junction (AJ) protein via the AKT/GSK3β pathway. In addition, rhFGF20 inhibited the cerebral inflammatory response through regulating the JNK/NFκB pathway and further protected the function of the BBB. Conclusions : Our results contribute to a new treatment strategy in TBI research. FGF20 is a potential candidate to treat TBI as it protects the BBB via regulating the AKT/GSK3β and JNK/NFκB signaling pathways.

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