scholarly journals HGG-10. THE BLOOD-BRAIN BARRIER IN DIPG: INVESTIGATING REGION-SPECIFIC DIFFERENCES IN PERMEABILITY

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i19-i19
Author(s):  
Caitlin Ung ◽  
Dannielle Upton ◽  
Maria Tsoli ◽  
David Ziegler
Keyword(s):  
Signaling Pathways ◽  
Blood Brain Barrier ◽  
Median Survival ◽  
High Grade Glioma ◽  
Brain Regions ◽  
Brain Barrier ◽  
Cortical Region ◽  
Blood Brain ◽  
The Impact

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is the most aggressive pediatric high-grade glioma with median survival of only 12 months from diagnosis. Current therapies are essentially palliative. The blood-brain barrier (BBB) is a major obstacle, limiting delivery of effective chemotherapeutics into the brain. We hypothesized that tumors in the brainstem region have a BBB less permeable than tumors in other brain regions. We have confirmed the presence of an intact BBB in three orthotopic models of DIPG by Evans Blue extravasation assay. Immunohistochemical staining of CD13+ pericytes and CD34+ endothelial cells in healthy mouse brain compared to orthotopic DIPG model showed higher levels of both components in brainstem compared to cortical region. Single-cell RNA sequencing experiments are currently being undertaken to investigate region-specific differences in BBB cell populations and the impact of DIPG on signaling pathways that govern permeability. To determine if tumor location impacts therapeutic outcome, we performed in vivo efficacy studies with DIPG orthotopically injected into cortical region or brainstem region and treated with SAHA, HDAC inhibitor, or temsirolimus, mTOR inhibitor. Temsirolimus or SAHA was ineffective at extending survival in mice injected with DIPG in the brainstem compared to control. However, temsirolimus led to a significant improvement in survival in mice injected with DIPG cells in cortical region (median survival 85 days) compared to control (median survival 69 days (P≤0.01)). This suggests that the same tumor in cortical region may respond to systemic therapy that is ineffective in the brainstem and that the intact BBB in the brainstem is a major reason for treatment failure in DIPG. In conclusion, the BBB in the brainstem and in the presence of DIPG may be altered, changing signaling pathways that affect permeability. Understanding the brainstem cerebrovasculature may potentially lead to a novel strategy to treat DIPG as well as other brain tumors.

Hypoxia increases glucose transport at blood-brain barrier in rats

1994 ◽  
Vol 77 (2) ◽  
pp. 896-901 ◽  
Author(s):  
S. I. Harik ◽  
R. A. Behmand ◽  
J. C. LaManna
Keyword(s):  
Glucose Transport ◽  
Blood Brain Barrier ◽  
Hypobaric Hypoxia ◽  
Cytochalasin B ◽  
Bolus Injection ◽  
Brain Regions ◽  
Brain Barrier ◽  
Cerebral Microvessels ◽  
Blood Brain

Prolonged hypoxia causes several adaptive changes in systemic physiology and tissue metabolism. We studied the effects of hypobaric hypoxia on glucose transport at the blood-brain barrier (BBB) in the rat. We found that hypoxia increased the density of brain microvessels seen on immunocytochemical stains using an antibody to the glucose transporting protein GLUT. In addition, we found that hypoxia increased the density of GLUT in isolated cerebral microvessels as determined by specific cytochalasin B binding. The higher GLUT density in isolated cerebral microvessels was evident after 1 wk of hypoxia and was associated with decreased activity of gamma-glutamyltranspeptidase. Consistent with these findings, we also demonstrated that 3 wk of hypobaric hypoxia caused increased unidirectional transport of glucose at the BBB in several brain regions in vivo, as determined by the doubly labeled single-pass indicator-fractionation atrial bolus injection method in anesthetized rats. We conclude that chronic hypobaric hypoxia is associated with increased glucose transport at the BBB.

scholarly journals Measurement of Blood—Brain Barrier Permeability with Positron Emission Tomography and [68Ga]EDTA

1984 ◽  
Vol 4 (3) ◽  
pp. 323-328 ◽  
Author(s):  
R. M. Kessler ◽  
J. C. Goble ◽  
J. H. Bird ◽  
M. E. Girton ◽  
J. L. Doppman ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Quantitative Measure ◽  
Brain Regions ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Blood Brain ◽  
Positron Emission ◽  
Area Product

Positron emission tomography (PET) was employed to examine time-dependent changes in blood–brain barrier (BBB) permeability to [68Ga]ethylenediaminetetraacetate (EDTA) in the rhesus monkey, following reversible barrier opening by intracarotid infusion of a hypertonic mannitol solution. The PET technique, when combined with measurements of plasma radioactivity, provided a quantitative measure of the cerebrovascular permeability-area product ( PA) at different times following mannitol infusion. Hypertonic mannitol treatment reversibly increased PA to [68Ga]EDTA more than 10-fold; much of the barrier effect was over by 10 min after mannitol treatment. The results show that PET can be used to measure transient changes in BBB integrity in specific brain regions, under in vivo, noninvasive conditions.

scholarly journals Blood-brain Barrier Crossing using Magnetic Stimulated Nanoparticles

2021 ◽  
Author(s):  
Jingfan Chen ◽  
Muzhaozi Yuan ◽  
Caitlin Madison ◽  
Shoshana Eitan ◽  
Ya Wang
Keyword(s):  
Blood Brain Barrier ◽  
Pbpk Model ◽  
Superparamagnetic Iron Oxide ◽  
Brain Barrier ◽  
Control Group ◽  
Pbpk Models ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly(ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.825) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the brain bioavailability under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47 % in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91 % compared to the group without SMF.

scholarly journals Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood–brain barrier

2021 ◽  
Author(s):  
Dominika Luptáková ◽  
Theodosia Vallianatou ◽  
Anna Nilsson ◽  
Reza Shariatgorji ◽  
Margareta Hammarlund-Udenaes ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
Mass Spectrometry Imaging ◽  
Brain Regions ◽  
Brain Barrier ◽  
Blood Brain ◽  
Comprehensive Determination

AbstractComprehensive determination of the extent of drug transport across the region-specific blood–brain barrier (BBB) is a major challenge in preclinical studies. Multiple approaches are needed to determine the regional free (unbound) drug concentration at which a drug engages with its therapeutic target. We present an approach that merges in vivo and in vitro neuropharmacokinetic investigations with mass spectrometry imaging to quantify and visualize both the extent of unbound drug BBB transport and the post-BBB cerebral distribution of drugs at regional and subregional levels. Direct imaging of the antipsychotic drugs risperidone, clozapine, and olanzapine using this approach enabled differentiation of regional and subregional BBB transport characteristics at 20-µm resolution in small brain regions, which could not be achieved by other means. Our approach allows investigation of heterogeneity in BBB transport and presents new possibilities for molecular psychiatrists by facilitating interpretation of regional target-site exposure results and decision-making.

scholarly journals Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia

Cephalalgia ◽  
2017 ◽  
Vol 38 (4) ◽  
pp. 674-689 ◽  
Author(s):  
Nathan T Fried ◽  
Christina R Maxwell ◽  
Melanie B Elliott ◽  
Michael L Oshinsky
Keyword(s):  
Blood Brain Barrier ◽  
Rat Model ◽  
Microglial Activation ◽  
Brain Regions ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Impact ◽  
Trigeminal Sensitivity

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.

Seizures Are Associated with Blood-Brain Barrier Disruption in a Piglet Model of Neonatal Hypoxic-Ischaemic Encephalopathy

2018 ◽  
Vol 40 (5-6) ◽  
pp. 560-575 ◽  
Author(s):  
Kate Goasdoue ◽  
Kirat Kishore Chand ◽  
Stephanie Melita Miller ◽  
Kah Meng Lee ◽  
Paul Bernard Colditz ◽  
...  
Keyword(s):  
Western Blot ◽  
Blood Brain Barrier ◽  
Parietal Cortex ◽  
Quantitative Polymerase Chain Reaction ◽  
Brain Regions ◽  
Brain Barrier ◽  
Matrix Metalloproteinase 2 ◽  
Preclinical Model ◽  
Blood Brain ◽  
The Impact

Seizures in the neonatal period are most often symptomatic of central nervous system (CNS) dysfunction and the most common cause is hypoxic-ischaemic encephalopathy (HIE). Seizures are associated with poor long-term outcomes and increased neuropathology. Blood-brain barrier (BBB) disruption and inflammation may contribute to seizures and increased neuropathology but are incompletely understood in neonatal HIE. The aim of this study was to investigate the impact of seizures on BBB integrity in a preclinical model of neonatal hypoxic-ischaemic (HI) injury. Piglets (age: <24 h) were subjected to a 30-min HI insult followed by recovery to 72 h post-insult. Amplitude-integrated electroencephalography (aEEG) was performed and seizure burden and background aEEG pattern were analysed. BBB disruption was evaluated in the parietal cortex and hippocampus by means of immunohistochemistry and Western blot. mRNA and protein expression of tight-junction proteins (zonula-occludens 1 [ZO1], occludin [OCLN], and claudin-5 [CLDN5]) was assessed using quantitative polymerase chain reaction (qPCR) and Western blot. In addition, mRNA from genes associated with BBB disruption vascular endothelial growth factor (VEGF) and matrix metalloproteinase 2 (MMP2) as well as inflammatory cytokines and chemokines was assessed with qPCR. Piglets that developed seizures following HI (HI-Sz) had significantly greater injury, as demonstrated by poorer aEEG background pattern scores, lower neurobehavioural scores, and greater histopathology. HI-Sz animals had severe IgG extravasation into brain tissue and uptake into neurons as well as significantly greater levels of IgG in both brain regions as assessed by Western blot. IgG protein in both brain regions was significantly associated with seizure burden, aEEG pattern scores, and neurobehavioural scores. There was no difference in mRNA expression of the tight junctions, however a significant loss of ZO1 and OCLN protein was observed in the parietal cortex. The inflammatory genes TGFβ, IL1β, IL8, IL6, and TNFα were significantly upregulated in HI-Sz animals. MMP2 was significantly increased in animals with seizures compared with animals without seizures. Increasing our understanding of neuropathology associated with seizure is vital because of the association between seizure and poor outcomes. Investigating the BBB is a major untapped area of research and a potential avenue for novel treatments.

On the Blood-Brain Barrier to Peptides: [3H]?Casomorphin-5 Uptake by Eighteen Brain Regions In Vivo

1983 ◽  
Vol 41 (5) ◽  
pp. 1229-1233 ◽  
Author(s):  
A. Ermisch ◽  
H.-J. Ruhle ◽  
K. Neubert ◽  
B. Hartrodt ◽  
R. Landgraf
Keyword(s):  
Blood Brain Barrier ◽  
Brain Regions ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals [18F]2-Fluoro-2-Deoxy-Sorbitol PET Imaging for Quantitative Monitoring of Enhanced Blood–Brain Barrier Permeability Induced by Focused Ultrasound

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1752
Author(s):  
Gaëlle Hugon ◽  
Sébastien Goutal ◽  
Ambre Dauba ◽  
Louise Breuil ◽  
Benoit Larrat ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Pet Imaging ◽  
Focused Ultrasound ◽  
Chemical Reduction ◽  
Imaging Techniques ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Impact

Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood–brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) was evaluated as a small-molecule (paracellular) marker of blood–brain barrier (BBB) integrity. [18F]FDS was straightforwardly produced from chemical reduction of commercial [18F]2-deoxy-2-fluoro-D-glucose. [18F]FDS and the invasive BBB integrity marker Evan’s blue (EB) were i.v. injected in mice after an optimized FUS protocol designed to generate controlled hemispheric BBB disruption. Quantitative determination of the impact of FUS on the BBB permeability was determined using kinetic modeling. A 2.2 ± 0.5-fold higher PET signal (n = 5; p < 0.01) was obtained in the sonicated hemisphere and colocalized with EB staining observed post mortem. FUS significantly increased the blood-to-brain distribution of [18F]FDS by 2.4 ± 0.8-fold (VT; p < 0.01). Low variability (=10.1%) of VT values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [18F]FDS PET provides a readily available, sensitive and reproducible marker of BBB permeability to noninvasively monitor the extent of BBB disruption induced by FUS in vivo.

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