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.

Functional impairment of blood-brain barrier following pesticide exposure during early development in rats

1999 ◽  
Vol 18 (3) ◽  
pp. 174-179 ◽  
Author(s):  
Alka Gupta ◽  
Renu Agarwal ◽  
Girja S Shukla
Keyword(s):  
Blood Brain Barrier ◽  
Repeated Exposure ◽  
Neurological Dysfunction ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Rat Pups ◽  
Blood Brain ◽  
Brain Uptake Index ◽  
Old Rats ◽  
Bbb Permeability

1 The effect of certain pesticides on the functional integrity of the developing blood-brain barrier (BBB) was studied following single and repeated exposure, and after subsequent withdrawal in rats. 2 Ten-day-old rat pups exposed orally to quinalphos (QP, organophosphate), cypermethrin (CM, pyre-throid) and lindane (LD, organochlorine) at a dose of 1/50th of LD50, showed a significant increase in the brain uptake index (BUI) for a micromolecular tracer, sodium fluorescein (SF), by 97, 37 and 72%, respectively, after 2 h. Residual increases in the BUI were found even after 3 days of the single treatment of QP (28%) and LD (23%). 3 Repeated exposure for 8 days (postnatal days (PND) 10-17) with QP, CM and LD increased the BBB permeability by 130, 80 and 50%, respectively. Recovery from these changes was complete in QP and LD-treated animals after 13 days (PND 18-30) of withdrawal. However, CM showed persistent effects that were normalized only after 43 days (PND 18-60) of withdrawal. 4 A single dose reduced to 1/100th of LD50 also increased BUI in 10-day-old rat pups following QP (20%) and CM (28%) exposure at 2 h. 5 An age-dependent effect of these pesticides was evident from the study showing higher magnitude of BUI changes in 10-day-old rats as compared to that in 15- day-old rats. Furthermore, adult rats did not show any effect on BBB permeability even at a higher dose (1/25th of LD50) of these pesticides given alone or in combination with piperonyl butoxide (600 mg/kg, i.p.) for 3 consecutive days. 6 This study showed that developing BBB is highly vulnerable to single or repeated exposure of certain pesticides. The observed persistent effects during brain development even after withdrawal of the treatment may produce some neurological dysfunction at later life as well.

scholarly journals The impact of microglial activation on blood-brain barrier in brain diseases

2014 ◽  
Vol 8 ◽  
Author(s):  
Anna Carolina Carvalho da Fonseca ◽  
Diana Matias ◽  
Celina Garcia ◽  
Rackele Amaral ◽  
Luiz Henrique Geraldo ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Microglial Activation ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain ◽  
The Impact

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.

scholarly journals Increased blood–brain barrier permeability is not a primary determinant for lethality of West Nile virus infection in rodents

2008 ◽  
Vol 89 (2) ◽  
pp. 467-473 ◽  
Author(s):  
John D. Morrey ◽  
Aaron L. Olsen ◽  
Venkatraman Siddharthan ◽  
Neil E. Motter ◽  
Hong Wang ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Blood Brain Barrier ◽  
Semliki Forest Virus ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
West Nile ◽  
Blood Brain ◽  
Lethal Infection ◽  
Primary Determinant ◽  
Bbb Permeability

Blood–brain barrier (BBB) permeability was evaluated in mice and hamsters infected with West Nile virus (WNV, flavivirus) as compared to those infected with Semliki Forest (alphavirus) and Banzi (flavivirus) viruses. BBB permeability was determined by measurement of fluorescence in brain homogenates or cerebrospinal fluid (CSF) after intraperitoneal (i.p.) injection of sodium fluorescein, by macroscopic examination of brains after i.p. injection of Evans blue, or by measurement of total protein in CSF compared to serum. Lethal infection of BALB/c mice with Semliki Forest virus and Banzi virus caused the brain : serum fluorescence ratios to increase from a baseline of 2–4 % to as high as 11 and 15 %, respectively. Lethal infection of BALB/c mice with WNV did not increase BBB permeability. When C57BL/6 mice were used, BBB permeability was increased in some, but not all, of the WNV-infected animals. A procedure was developed to measure BBB permeability in live WNV-infected hamsters by comparing the fluorescence in the CSF, aspirated from the cisterna magnum, with the fluorescence in the serum. Despite a time-dependent tendency towards increased BBB permeability in some WNV-infected hamsters, the highest BBB permeability values did not correlate with mortality. These data indicated that a measurable increase in BBB permeability was not a primary determinant for lethality of WNV infection in rodents. The lack of a consistent increase in BBB permeability in WNV-infected rodents has implications for the understanding of viral entry, viral pathogenesis and accessibility of the CNS of rodents to drugs or effector molecules.

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.

scholarly journals Effects of acute hypoxia and hyperthermia on the permeability of the blood-brain barrier in adult rats

2009 ◽  
Vol 107 (4) ◽  
pp. 1348-1356 ◽  
Author(s):  
Sirajedin S. Natah ◽  
Sathya Srinivasan ◽  
Quentin Pittman ◽  
Zonghang Zhao ◽  
Jeff F. Dunn
Keyword(s):  
High Altitude ◽  
Blood Brain Barrier ◽  
Vasogenic Edema ◽  
Acute Hypoxia ◽  
Acute Mountain Sickness ◽  
Brain Barrier ◽  
Adaptation To Hypoxia ◽  
Sodium Fluorescein ◽  
Blood Brain ◽  
Bbb Permeability

Acute mountain sickness (AMS) develops within a few hours after arrival at high altitude and includes headache, anorexia, nausea, vomiting, and malaise. This afflicts 15–25% of the general tourist population at moderate altitudes. High-altitude cerebral edema (HACE) is considered to be the end stage of severe AMS and has been suggested to be a vasogenic edema, raising the possibility that acute hypoxia may increase blood-brain barrier (BBB) permeability. At present, there are no good small-animal models to study this syndrome. We hypothesize 1) that acute hypoxia can damage the BBB and 2) that rat can be used as a model to study hypoxia-induced changes in BBB permeability, especially if hypoxia-induced hypothermia could be minimized with high ambient temperature (HAT). Male Wistar rats were exposed to 1, 2, and 7 days of hypobaric hypoxia (equivalent to 0.5 atm), and changes in the temperature and BBB permeability were studied. The extravasation of endogenous immunoglobulin G, a large molecule, did not increase during room temperature hypoxia but did increase when hypoxia was combined with HAT. Hypoxia caused a significant increase in the leakage of sodium fluorescein (mol wt 376 Da). The expression of endothelial barrier antigen (EBA), a protein associated with the BBB, was reduced to 50% between 24 and 48 h after exposure to hypoxia, and the loss was exacerbated by HAT. The values almost returned to control levels by 7 days, showing adaptation to hypoxia. Hypoxic rats exhibited sodium fluorescein leakage mainly in focal areas in the brain parenchyma. In conclusion, it is possible to have transient BBB damage through exposure to acute hypoxia, and this damage is exacerbated by increasing body temperature to more of a normothermic value.

scholarly journals Comparative Effects of Glucose- and Mannitol-Induced Osmolar Stress on Blood—Brain Barrier Function in Ovine Fetuses and Lambs

2011 ◽  
Vol 32 (1) ◽  
pp. 115-126 ◽  
Author(s):  
Barbara S Stonestreet ◽  
Grazyna B Sadowska ◽  
R Choudary Hanumara ◽  
Mihaela Petrache ◽  
Katherine H Petersson ◽  
...  
Keyword(s):  
Superior Colliculus ◽  
Blood Brain Barrier ◽  
Brain Regions ◽  
Brain Barrier ◽  
Transfer Constant ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Relationship ◽  
Segmented Regression Model ◽  
Colliculus Inferior

We examined the effects of hyperglycemic hyperosmolality on blood-brain barrier (BBB) permeability during development. We hypothesized that the barrier becomes more resistant to hyperglycemic hyperosmolality during development, and the immature BBB is more resistant to glucose than to mannitol hyperosmolality. We quantified the BBB response to hyperosmolality with the blood-to-brain transfer constant ( Ki) in immature fetuses, premature, and newborn lambs. Ki increased as a function of increases in osmolality. A segmented regression model described the relationship between Ki and osmolality. At lower osmolalities, changes in Ki were minimal but after a threshold, increases were linear. We examined responses of Ki to hyperglycemic hyperosmolality by comparing the thresholds and slopes of the second regression segments. Lower thresholds and steeper slopes indicate greater vulnerability to hyperosmolality. Thresholds increased ( P < 0.05) during development in pons and superior colliculus. Thresholds were higher ( P < 0.05) during glucose than mannitol hyperosmolality in thalamus, superior colliculus, inferior colliculus and medulla of premature lambs, and in cerebrum and cerebellum of newborns. We conclude that BBB permeability increased as a function of changes in glucose osmolality, the barrier becomes more resistant to glucose hyperosmolality in two brain regions during development, and the barrier is more resistant to glucose than to mannitol hyperosmolality in some brain regions of premature and newborn lambs.

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.

scholarly journals Apolipoprotein M-bound sphingosine-1-phosphate regulates blood–brain barrier paracellular permeability and transcytosis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Mette Mathiesen Janiurek ◽  
Rana Soylu-Kucharz ◽  
Christina Christoffersen ◽  
Krzysztof Kucharz ◽  
Martin Lauritzen
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Cerebral Microvessels ◽  
Apolipoprotein M ◽  
Two Photon Microscopy ◽  
Blood Brain ◽  
Sphingosine 1 Phosphate ◽  
Pial Arterioles ◽  
Bbb Permeability

The blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels, but how blood-borne signaling molecules influence permeability is incompletely understood. We here examined how the apolipoprotein M (apoM)-bound sphingosine 1–phosphate (S1P) signaling pathway affects the BBB in different categories of cerebral microvessels using ApoM deficient mice (Apom-/-). We used two-photon microscopy to monitor BBB permeability of sodium fluorescein (376 Da), Alexa Fluor (643 Da), and fluorescent albumin (45 kDA). We show that BBB permeability to small molecules increases in Apom-/- mice. Vesicle-mediated transfer of albumin in arterioles increased 3 to 10-fold in Apom-/- mice, whereas transcytosis in capillaries and venules remained unchanged. The S1P receptor 1 agonist SEW2871 rapidly normalized paracellular BBB permeability in Apom-/- mice, and inhibited transcytosis in penetrating arterioles, but not in pial arterioles. Thus, apoM-bound S1P maintains low paracellular BBB permeability in all cerebral microvessels and low levels of vesicle-mediated transport in penetrating arterioles.

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