Development of an In Vitro 3D Brain Tissue Model Mimicking In Vivo-Like Pro-inflammatory and Pro-oxidative Responses

Background: Inflammation is a hallmark of epileptogenic brain tissue. Previously, we have shown that inflammation in epilepsy can be delineated using systemically-injected fluorescent and magnetite- laden nanoparticles. Suggested mechanisms included distribution of free nanoparticles across a compromised blood-brain barrier or their transfer by monocytes that infiltrate the epileptic brain. Objective: In the current study, we evaluated monocytes as vehicles that deliver nanoparticles into the epileptic brain. We also assessed the effect of epilepsy on the systemic distribution of nanoparticleloaded monocytes. Methods: The in vitro uptake of 300-nm nanoparticles labeled with magnetite and BODIPY (for optical imaging) was evaluated using rat monocytes and fluorescence detection. For in vivo studies we used the rat lithium-pilocarpine model of temporal lobe epilepsy. In vivo nanoparticle distribution was evaluated using immunohistochemistry. Results: 89% of nanoparticle loading into rat monocytes was accomplished within 8 hours, enabling overnight nanoparticle loading ex vivo. The dose-normalized distribution of nanoparticle-loaded monocytes into the hippocampal CA1 and dentate gyrus of rats with spontaneous seizures was 176-fold and 380-fold higher compared to the free nanoparticles (p<0.05). Seizures were associated with greater nanoparticle accumulation within the liver and the spleen (p<0.05). Conclusion: Nanoparticle-loaded monocytes are attracted to epileptogenic brain tissue and may be used for labeling or targeting it, while significantly reducing the systemic dose of potentially toxic compounds. The effect of seizures on monocyte biodistribution should be further explored to better understand the systemic effects of epilepsy.

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In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.5.1091 ◽

1999 ◽

Vol 43 (5) ◽

pp. 1091-1097 ◽

Cited By ~ 7

Author(s):

Hideki Kita ◽

Hirotami Matsuo ◽

Hitomi Takanaga ◽

Junichi Kawakami ◽

Koujirou Yamamoto ◽

...

Keyword(s):

Brain Tissue ◽

Threshold Concentration ◽

Current Response ◽

Drug Induced ◽

Inhibition Ratio ◽

New Quinolones ◽

The Central Nervous System ◽

Anti Inflammatory

ABSTRACT We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the γ-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 μM) > FRP (0.3 μM) > FLB (0.2 μM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

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In VitroandIn VivoEvaluation of APX001A/APX001 and Other Gwt1 Inhibitors againstCryptococcus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00523-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 34

Author(s):

Karen Joy Shaw ◽

Wiley A. Schell ◽

Jonathan Covel ◽

Gisele Duboc ◽

C. Giamberardino ◽

...

Keyword(s):

Brain Tissue ◽

Lung Tissue ◽

Fungal Infections ◽

Treatment Options ◽

Content Type ◽

Fungal Burden ◽

Geographical Regions ◽

Current Therapies

ABSTRACTCryptococcal meningitis (CM), caused primarily byCryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated thein vitroandin vivoactivity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against bothC. neoformansandC. gattii. APX001A and APX2020 demonstratedin vitrosynergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log10CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10CFU/g lung tissue and from 7.00 and 0.92 log10CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM.

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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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Genomics Analysis of Metabolic Pathways of Human Stem Cell-Derived Microglia-Like Cells and the Integrated Cortical Spheroids

Stem Cells International ◽

10.1155/2019/2382534 ◽

2019 ◽

Vol 2019 ◽

pp. 1-21 ◽

Cited By ~ 7

Author(s):

Julie Bejoy ◽

Xuegang Yuan ◽

Liqing Song ◽

Thien Hua ◽

Richard Jeske ◽

...

Keyword(s):

Brain Tissue ◽

Metabolic Pathways ◽

Disease Modeling ◽

Aerobic Glycolysis ◽

Three Dimensional ◽

Initiation Factor ◽

Human Brain Tissue ◽

P53 Signaling

Brain spheroids or organoids derived from human pluripotent stem cells (hiPSCs) are still not capable of completely recapitulating in vivo human brain tissue, and one of the limitations is lack of microglia. To add built-in immune function, coculture of the dorsal forebrain spheroids with isogenic microglia-like cells (D-MG) was performed in our study. The three-dimensional D-MG spheroids were analyzed for their transcriptome and compared with isogenic microglia-like cells (MG). Cortical spheroids containing microglia-like cells displayed different metabolic programming, which may affect the associated phenotype. The expression of genes related to glycolysis and hypoxia signaling was increased in cocultured D-MG spheroids, indicating the metabolic shift to aerobic glycolysis, which is in favor of M1 polarization of microglia-like cells. In addition, the metabolic pathways and the signaling pathways involved in cell proliferation, cell death, PIK3/AKT/mTOR signaling, eukaryotic initiation factor 2 pathway, and Wnt and Notch pathways were analyzed. The results demonstrate the activation of mTOR and p53 signaling, increased expression of Notch ligands, and the repression of NF-κB and canonical Wnt pathways, as well as the lower expression of cell cycle genes in the cocultured D-MG spheroids. This analysis indicates that physiological 3-D microenvironment may reshape the immunity of in vitro cortical spheroids and better recapitulate in vivo brain tissue function for disease modeling and drug screening.

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The biosynthesis of cholesterol and other sterols by brain tissue: II. A comparison of in vitro and in vivo methods

Lipids ◽

10.1007/bf02538392 ◽

1971 ◽

Vol 6 (4) ◽

pp. 225-232 ◽

Cited By ~ 13

Author(s):

R. B. Ramsey ◽

J. P. Jones ◽

S. H. M. Naqvi ◽

H. J. Nicholas

Keyword(s):

Brain Tissue

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Brain tissue binding explains discrepancy between in vitro and in vivo methods for assessing blood–brain barrier permeability of chemicals

Toxicology Letters ◽

10.1016/j.toxlet.2017.07.300 ◽

2017 ◽

Vol 280 ◽

pp. S107

Author(s):

Marjolein Heymans ◽

Emmanuel Sevin ◽

Fabien Gosselet ◽

Maxime Culot

Keyword(s):

Brain Tissue ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Tissue Binding ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability

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Multiple Irradiation Affects Cellular and Extracellular Components of the Mouse Brain Tissue and Adhesion and Proliferation of Glioblastoma Cells in Experimental System In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms222413350 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13350

Author(s):

Maxim O. Politko ◽

Alexandra Y. Tsidulko ◽

Oxana A. Pashkovskaya ◽

Konstantin E. Kuper ◽

Anastasia V. Suhovskih ◽

...

Keyword(s):

Brain Tissue ◽

Mouse Brain ◽

Glial Cells ◽

Ex Vivo ◽

Experimental System ◽

Normal Brain ◽

Biosynthetic Activity ◽

Normal Brain Tissue

Intensive adjuvant radiotherapy (RT) is a standard treatment for glioblastoma multiforme (GBM) patients; however, its effect on the normal brain tissue remains unclear. Here, we investigated the short-term effects of multiple irradiation on the cellular and extracellular glycosylated components of normal brain tissue and their functional significance. Triple irradiation (7 Gy*3 days) of C57Bl/6 mouse brain inhibited the viability, proliferation and biosynthetic activity of normal glial cells, resulting in a fast brain-zone-dependent deregulation of the expression of proteoglycans (PGs) (decorin, biglycan, versican, brevican and CD44). Complex time-point-specific (24–72 h) changes in decorin and brevican protein and chondroitin sulfate (CS) and heparan sulfate (HS) content suggested deterioration of the PGs glycosylation in irradiated brain tissue, while the transcriptional activity of HS-biosynthetic system remained unchanged. The primary glial cultures and organotypic slices from triple-irradiated brain tissue were more susceptible to GBM U87 cells’ adhesion and proliferation in co-culture systems in vitro and ex vivo. In summary, multiple irradiation affects glycosylated components of normal brain extracellular matrix (ECM) through inhibition of the functional activity of normal glial cells. The changed content and pattern of PGs and GAGs in irradiated brain tissues are accompanied by the increased adhesion and proliferation of GBM cells, suggesting a novel molecular mechanism of negative side-effects of anti-GBM radiotherapy.

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