Identification of a Transversely Isotropic Material Model for White Matter in the Brain

2012 ◽  
Author(s):  
Yuan Feng ◽  
Ruth J. Okamoto ◽  
Ravi Namani ◽  
Guy M. Genin ◽  
Philip V. Bayly
Keyword(s):  
Brain Injury ◽  
White Matter ◽  
Mechanical Anisotropy ◽  
Accurate Information ◽  
In Vitro Tests ◽  
Fiber Direction ◽  
Structural Anisotropy ◽  
Axonal Fiber ◽  
The Brain

Axonal fiber tracts in white matter of the brain form anisotropic structures. It is assumed that this structural anisotropy causes mechanical anisotropy, making white matter tissue stiffer along the axonal fiber direction. This, in turn, will affect the mechanical loading of axonal tracts during traumatic brain injury (TBI). The goal of this study is to use a combination of in-vitro tests to characterize the mechanical anisotropy of white matter and compare it to gray matter, which is thought to be structurally and mechanically isotropic. A more complete understanding of the mechanical anisotropy of brain tissue will provide more accurate information for computational simulations of brain injury.

Abstract P747: Gpr68 Play a Protective Role in Ischemic Stroke in Mice

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
tao wang ◽  
Guokun Zhou ◽  
mingdi he ◽  
yuanyuan xu ◽  
w.g. Rusyniak ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Neuronal Injury ◽  
Protective Role ◽  
Functional Screening ◽  
Rt Pcr ◽  
Brain Neurons ◽  
Acid Sensing Ion Channels ◽  
The Brain

Introduction: Acidosis is one prevalent phenomenon in ischemic stroke. The literature has shown that protons directly gate acid-sensing ion channels (ASICs) and proton-activated chloride channel, both lead to neuronal injury However, it is unclear whether protons activate metabotropic pathways in brain neurons. There are four proton-sensitive G-protein coupled receptors (GPCRs): GPR4, GPR65, GPR68 and GPR132. It remains unknown whether any of these GPCRs mediate acid-induced signals in brain neurons or whether they contribute to ischemia-induced brain injury. Methods: Total RNA from human cortical tissue or mouse brain was isolated using TRIzol and an RNase Kit. Standard RT-PCR was performed to determine the expression of these GPCRs in the brain. An in vitro slice injury model was used for functional screening. To determine the effect of ischemia, WT and knockout male mice were subjected to MCAO. To study brain injury, brains were sectioned coronally at 1 mm intervals and stained by vital dye immersion: (2%) 2,3,5-triphenyltetrazolium hydrochloride (TTC). Locomotor analysis and corner test were used to assess behavior outcome. Adeno-associated virus (AAV) -mediated gene delivery was used to determine the outcome of GPR68 overexpression. Results: RT-PCR showed that brain tissue expressed GPR4, -65, and -68. The expression of GPR68 was evident at 30 cycles. In organotypic slices, compared to the WT, deleting GPR4 or GPR65 had no effect while deleting GPR68 significantly increased acidosis-induced neuronal injury. At both 24 hour and 72 hour after 45 minutes MCAO, GPR68 deletion increased brain injury (p=0.0020 for 24hour, p=0.0392 for 72hour, Mann-Whitney U test). WT and GPR68-/- mice did not differ in baseline locomotor activities or corner test. On the third day following MCAO, GPR68-/- exhibited significantly more left rotations (p=0.0287, Mann-Whitney U test) than WT animals. Lastly, mice receiving AAV-GPR68 exhibited an average infarct of 21.97 ± 12.4%, significantly (p = 0.0022, Mann-Whitney U test) smaller than those receiving AAV-GFP (37.2 ± 6.8%). Conclusion: These data showed that GPR68 functions as a neuroprotective proton receptor in the brain.

scholarly journals Transplanted Oligodendrocyte Progenitor Cells Survive in the Brain of a Rat Neonatal White Matter Injury Model but Less Mature in Comparison with the Normal Brain

2020 ◽  
Vol 29 ◽  
pp. 096368972094609
Author(s):  
Shino Ogawa ◽  
Mutsumi Hagiwara ◽  
Sachiyo Misumi ◽  
Naoki Tajiri ◽  
Takeshi Shimizu ◽  
...  
Keyword(s):  
White Matter ◽  
Replacement Therapy ◽  
Fluorescent Protein ◽  
White Matter Injury ◽  
Normal Brain ◽  
Cell Replacement Therapy ◽  
Cell Replacement ◽  
Vitro Effect ◽  
The Brain

Preterm infants have a high risk of neonatal white matter injury (WMI) caused by hypoxia-ischemia. Cell-based therapies are promising strategies for neonatal WMI by providing trophic substances and replacing lost cells. Using a rat model of neonatal WMI in which oligodendrocyte progenitors (OPCs) are predominantly damaged, we investigated whether insulin-like growth factor 2 (IGF2) has trophic effects on OPCs in vitro and whether OPC transplantation has potential as a cell replacement therapy. Enhanced expression of Igf2 mRNA was first confirmed in the brain of P5 model rats by real-time polymerase chain reaction. Immunostaining for IGF2 and its receptor IGF2 R revealed that both proteins were co-expressed in OLIG2-positive and GFAP-positive cells in the corpus callosum (CC), indicating autocrine and paracrine effects of IGF2. To investigate the in vitro effect of IGF2 on OPCs, IGF2 (100 ng/ml) was added to the differentiation medium containing ciliary neurotrophic factor (10 ng/ml) and triiodothyronine (20 ng/ml), and IGF2 promoted the differentiation of OPCs into mature oligodendrocytes. We next transplanted rat-derived OPCs that express green fluorescent protein into the CC of neonatal WMI model rats without immunosuppression and investigated the survival of grafted cells for 8 weeks. Although many OPCs survived for at least 8 weeks, the number of mature oligodendrocytes was unexpectedly small in the CC of the model compared with that in the sham-operated control. These findings suggest that the mechanism in the brain that inhibits differentiation should be solved in cell replacement therapy for neonatal WMI as same as trophic support from IGF2.

scholarly journals SCIDOT-34. BRAIN INJURY SIGNALS SYSTEMIC IMMUNOSUPPRESSION THROUGH THYMIC INVOLUTION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi278-vi279
Author(s):  
Katayoun Ayasoufi ◽  
Christian K Pfaller ◽  
Roman H Khadka ◽  
Fang Jin ◽  
Jiaying Zheng ◽  
...  
Keyword(s):  
Brain Injury ◽  
T Cell ◽  
Thymic Involution ◽  
Systemic Immunosuppression ◽  
Cell Counts ◽  
Immune Deficiencies ◽  
Underlying Mechanisms ◽  
Neurological Injuries ◽  
The Brain

Abstract Systemic immunosuppression following neurological insults including stroke, traumatic brain injury, and glioblastoma (GBM) causes mortality and leads to failure of immune-modulating therapies. Exact immunological nature and the underlying mechanisms of this immunosuppression are unknown. Our goal was to define effects of neurological insults given exclusively to the brain on the thymus. The thymus is the primary immune organ responsible for T-cell development and maintenance both in children and in adults. We evaluated the brain-thymus communication using the following neurological insults: physical injury, CNS viral infection, sterile injury, tumor implantation, and seizures. All insults resulted in significant thymic involution that was reversible upon clearance of the insult. Thymic involution did not occur following similar peripheral insults. We next demonstrated that the GL261 model of GBM recapitulates hallmark features of peripheral immunosuppression observed in GBM patients including low CD4 T-cell counts. Thus, we aimed to further study the immunosuppression affecting the thymus in this clinically relevant model. Principle component analysis following RNA-sequencing of thymi from naïve and glioma-bearing mice revealed unbiased separation of the groups suggesting that the thymus is directly affected by a brain tumor. To determine the extent to which thymic involution was caused by a soluble factor we employed parabiosis. We demonstrated that thymic involution was transferable from glioma-bearing to non-tumor-bearing parabionts. Similarly, serum taken from GL261 glioma-bearing mice potently inhibited proliferation of T-cells in vitro. Together our data demonstrate that CNS-specific insults, regardless of nature, cause immunosuppression by prompting thymic involution through circulating factors. This accounts at least partially for immune deficiencies observed following neurological injuries. Identification of this suppressive factor is crucial in designing future therapeutics for GBM patients, and patients with other acute and chronic neurological trauma.

scholarly journals ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

2015 ◽  
Vol 36 (4) ◽  
pp. 1539-1551 ◽  
Author(s):  
Qian Yu ◽  
Zhihong Lu ◽  
Lei Tao ◽  
Lu Yang ◽  
Yu Guo ◽  
...  
Keyword(s):  
Brain Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
In Vivo Models ◽  
The Brain

Background/Aims: Stroke is among the top causes of death worldwide. Neuroprotective agents are thus considered as potentially powerful treatment of stroke. Methods: Using both HT22 cells and male Sprague-Dawley rats as in vitro and in vivo models, we investigated the effect of NaHS, an exogenous donor of H2S, on the focal cerebral ischemia-reperfusion (I/R) induced brain injury. Results: Administration of NaHS significantly decreased the brain infarcted area as compared to the I/R group in a dose-dependent manner. Mechanistic studies demonstrated that NaHS-treated rats displayed significant reduction of malondialdehyde content, and strikingly increased activity of superoxide dismutases and glutathione peroxidase in the brain tissues compared with I/R group. The enhanced antioxidant capacity as well as restored mitochondrial function are NaHS-treatment correlated with decreased cellular reactive oxygen species level and compromised apoptosis in vitro or in vivo in the presence of NaHS compared with control. Further analysis revealed that the inhibition of PARP-1 cleavage and AIF translocation are involved in the neuroprotective effects of NaHS. Conclusion: Collectively, our results suggest that NaHS has potent protective effects against the brain injury induced by I/R. NaHS is possibly effective through inhibition of oxidative stress and apoptosis.

Anisotropic Behavior of White Matter in Shear and Implications for Transversely Isotropic Models

2013 ◽  
Author(s):  
Ruth J. Okamoto ◽  
Yuan Feng ◽  
Guy M. Genin ◽  
Philip V. Bayly
Keyword(s):  
White Matter ◽  
Strain Tensor ◽  
Experimental Studies ◽  
Transversely Isotropic ◽  
Stretch Ratio ◽  
Fiber Axis ◽  
Fiber Direction ◽  
Material Models ◽  
Green Strain ◽  
The Brain

Experimental studies [1] have shown that white matter (WM) in the brain is mechanically anisotropic. Based on its fibrous structure, transversely isotropic (TI) material models have been suggested to capture WM behavior. TI hyperelastic material models involve strain energy density functions that depend on the I4 and I5 pseudo-invariants of the Cauchy-Green strain tensor to account for the effects of stiff fibers. The pseudo-invariant I4 is the square of the stretch ratio in the fiber direction; I5 contains contributions of shear strain in planes parallel to the fiber axis. Most, if not all, published models of WM depend on I4 but not on I5.

scholarly journals Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice

2019 ◽  
Author(s):  
Xin-chun Ye ◽  
Qi Hao ◽  
Wei-jing Ma ◽  
Qiu-chen Zhao ◽  
Wei-wei Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Infarct Volume ◽  
Inos Expression ◽  
Microglial Cells ◽  
Brain Infarct ◽  
Tnf Α ◽  
Bv2 Microglial Cells ◽  
The Brain

Abstract Dendritic cell-associated C-type lectin-1 (Dectin-1) receptor has been reported to be involved in neuroinflammation in Alzheimer's disease and traumatic brain injury. The present study was designed to investigate the role of Dectin-1 and its downstream target spleen tyrosine kinase (Syk) in early brain injury after ischemic stroke using a focal cortex ischemic stroke model. Adult male C57BL/6J mice were subjected to a cerebral focal ischemia model of ischemic stroke. The neurological score, adhesive removal test and foot-fault test were evaluated on days 1, 3, 5 and 7 after ischemic stroke. Dectin-1, Syk, phosphorylated (p)-Syk, tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression was analyzed via western blotting in ischemic brain tissue after ischemic stroke and in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro. The brain infarct volume and Iba1-positive cells were evaluated using Nissl’s and immunofluorescence staining, respectively. The Dectin-1 antagonist laminarin (LAM) and a selective inhibitor of Syk phosphorylation (piceatannol; PIC) were used for the intervention. Dectin-1, Syk, and p-Syk expression was significantly enhanced on days 3, 5 and 7 and peaked on day 3 after ischemic stroke. The Dectin-1 antagonist LAM or Syk inhibitor PIC decreased the number of Iba1-positive cells and TNF-α and iNOS expression, decreased the brain infarct volume and improved neurological functions on day 3 after ischemic stroke. In addition, the in vitro data revealed that Dectin-1, Syk and p-Syk expression was increased following the 3-h OGD and 0, 3 and 6 h of reperfusion in BV2 microglial cells. LAM and PIC also decreased TNF-α and iNOS expression 3 h after OGD/R induction. Dectin-1/Syk signaling plays a crucial role in inflammatory activation after ischemic stroke, and further investigation of Dectin-1/Syk signaling in stroke is warranted.

The Development of Structural and Mechanical Anisotropy in Fibroblast Populated Collagen Gels

2005 ◽  
Vol 127 (5) ◽  
pp. 742-750 ◽  
Author(s):  
Stavros Thomopoulos ◽  
Gregory M. Fomovsky ◽  
Jeffrey W. Holmes
Keyword(s):  
Structure Function ◽  
Collagen Gel ◽  
Cell Types ◽  
Model System ◽  
Mechanical Anisotropy ◽  
Collagen Gels ◽  
Structural Anisotropy ◽  
Mechanical Constraints ◽  
Collagenous Tissues

An in vitro model system was developed to study structure-function relationships and the development of structural and mechanical anisotropy in collagenous tissues. Fibroblast-populated collagen gels were constrained either biaxially or uniaxially. Gel remodeling, biaxial mechanical properties, and collagen orientation were determined after 72h of culture. Collagen gels contracted spontaneously in the unconstrained direction, uniaxial mechanical constraints produced structural anisotropy, and this structural anisotropy was associated with mechanical anisotropy. Cardiac and tendon fibroblasts were compared to test the hypothesis that tendon fibroblasts should generate greater anisotropy in vitro. However, no differences were seen in either structure or mechanics of collagen gels populated with these two cell types, or between fibroblast populated gels and acellular gels. This study demonstrates our ability to control and measure the development of structural and mechanical anisotropy due to imposed mechanical constraints in a fibroblast-populated collagen gel model system. While imposed constraints were required for the development of anisotropy in this system, active remodeling of the gel by fibroblasts was not. This model system will provide a basis for investigating structure-function relationships in engineered constructs and for studying mechanisms underlying the development of anisotropy in collagenous tissues.

scholarly journals Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Brain Levels of Drug in Rat

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1402
Author(s):  
Bárbara Sánchez-Dengra ◽  
Isabel Gonzalez-Alvarez ◽  
Marival Bermejo ◽  
Marta Gonzalez-Alvarez
Keyword(s):  
High Throughput Screening ◽  
Pbpk Model ◽  
Screening Tools ◽  
Pbpk Modeling ◽  
In Vitro Tests ◽  
Structure Property ◽  
Scaling Factors ◽  
Internal Validation ◽  
The Brain

One of the main obstacles in neurological disease treatment is the presence of the blood–brain barrier. New predictive high-throughput screening tools are essential to avoid costly failures in the advanced phases of development and to contribute to the 3 Rs policy. The objective of this work was to jointly develop a new in vitro system coupled with a physiological-based pharmacokinetic (PBPK) model able to predict brain concentration levels of different drugs in rats. Data from in vitro tests with three different cells lines (MDCK, MDCK-MDR1 and hCMEC/D3) were used together with PK parameters and three scaling factors for adjusting the model predictions to the brain and plasma profiles of six model drugs. Later, preliminary quantitative structure–property relationships (QSPRs) were constructed between the scaling factors and the lipophilicity of drugs. The predictability of the model was evaluated by internal validation. It was concluded that the PBPK model, incorporating the barrier resistance to transport, the disposition within the brain and the drug–brain binding combined with MDCK data, provided the best predictions for passive diffusion and carrier-mediated transported drugs, while in the other cell lines, active transport influence can bias predictions.

scholarly journals Diverse Changes in Microglia Morphology and Axonal Pathology Over One Year after Mild Traumatic Brain Injury in Pigs

2020 ◽  
Author(s):  
Michael R. Grovola ◽  
Nicholas Paleologos ◽  
Daniel P. Brown ◽  
Nathan Tran ◽  
Kathryn L. Wofford ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Mild Traumatic Brain Injury ◽  
Periventricular White Matter ◽  
Post Injury ◽  
Mild Tbi ◽  
Time Points ◽  
Axonal Pathology ◽  
The Brain

AbstractOver 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that occur due to TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1 year post injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1 year post injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.

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