Quantitative autoradiographic measurements of blood-brain barrier permeability in the rat glioma model

1982 ◽  
Vol 57 (3) ◽  
pp. 394-398 ◽  
Author(s):  
Kazuo Yamada ◽  
Yukitaka Ushio ◽  
Toru Hayakawa ◽  
Amami Kato ◽  
Noriko Yamada ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Chemotherapeutic Drugs ◽  
Content Type ◽  
Rat Glioma ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Bbb Permeability ◽  
Autoradiographic Technique ◽  
The Brain

✓ Quantitative autoradiographic technique was applied in measuring blood-brain barrier (BBB) permeability of autochthonous gliomas in rats. In small tumors (less than 2 mm in diameter), no increase in BBB permeability was noted. As the tumor grew and neovascularization occurred, BBB permeability increased in the center of the tumor, and it was suggested that the BBB was partly disrupted in the neovascularized vessels. In the fully grown tumors, BBB permeability was markedly increased in the viable part of the tumor to levels similar to the choroid plexus. Yet, the BBB was partly preserved at the periphery of the tumor and in the brain adjacent to the tumor. The heterogeneity of the BBB phenomenon according to the stage of tumor growth may be a major obstacle for uptake of chemotherapeutic drugs that do not cross the BBB easily.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

scholarly journals Penetration of the blood-brain barrier: enhancement of drug delivery and imaging by bacterial glycopeptides.

1995 ◽  
Vol 182 (4) ◽  
pp. 1037-1043 ◽  
Author(s):  
B Spellerberg ◽  
S Prasad ◽  
C Cabellos ◽  
M Burroughs ◽  
P Cahill ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Pharmacological Agents ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Brain

The blood-brain barrier restricts the passage of many pharmacological agents into the brain parenchyma. Bacterial glycopeptides induce enhanced blood-brain barrier permeability when they are present in the subarachnoid space during meningitis. By presenting such glycopeptides intravenously, blood-brain barrier permeability in rabbits was enhanced in a reversible time- and dose-dependent manner to agents < or = 20 kD in size. Therapeutic application of this bioactivity was evident as enhanced penetration of the antibiotic penicillin and the magnetic resonance imaging contrast agent gadolinium-diethylene-triamine-pentaacetic acid into the brain parenchyma.

scholarly journals Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

2020 ◽  
Vol 13 (10) ◽  
pp. 279
Author(s):  
Dina Sikpa ◽  
Lisa Whittingstall ◽  
Martin Savard ◽  
Réjean Lebel ◽  
Jérôme Côté ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Drug Delivery ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Radiation Induced ◽  
B2 Receptors ◽  
Peptide Agonist ◽  
The Brain

The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.

scholarly journals EXTH-02. THE BLOOD BRAIN BARRIER (BBB) PERMEABILITY IS ALTERED BY TUMOR TREATING FIELDS (TTFIELDS) IN VIVO

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi82-vi82 ◽  
Author(s):  
Ellina Schulz ◽  
Almuth F Kessler ◽  
Ellaine Salvador ◽  
Dominik Domröse ◽  
Malgorzata Burek ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Dce Mri ◽  
Tumor Treating Fields ◽  
Blood Brain ◽  
Vessel Structure ◽  
Bbb Permeability ◽  
The Brain

Abstract OBJECTIVE For glioblastoma patients Tumor Treating Fields (TTFields) have been established as adjuvant therapy. The blood brain barrier (BBB) tightly controls the influx of the majority of compounds from blood to brain. Therefore, the BBB may block delivery of drugs for treatment of brain tumors. Here, the influence of TTFields on BBB permeability was assessed in vivo. METHODS Rats were treated with 100 kHz TTFields for 72 h and thereupon i.v. injected with Evan’s Blue (EB) which directly binds to Albumin. To evaluate effects on BBB, EB was extracted after brain homogenization and quantified. In addition, cryosections of rat brains were prepared following TTFields application. The sections were stained for tight junction proteins Claudin-5 and Occludin and for immunoglobulin G (IgG) to assess vessel structure. Furthermore, serial dynamic contrast-enhanced DCE-MRI with Gadolinium contrast agent was performed before and after TTFields application. RESULTS TTFields application significantly increased the EB accumulation in the rat brain. In TTFields-treated rats, the vessel structure became diffuse compared to control cryosections of rat brains; Claudin 5 and Occludin were delocalized and IgG was found throughout the brain tissue. Serial DCE-MRI demonstrated significantly increased accumulation of Gadolinium in the brain, observed directly after 72 h of TTFields application. The effect of TTFields on the BBB disappeared 96 h after end of treatment and no difference in contrast enhancement between controls and TTFields treated animals was detectable. CONCLUSION By altering BBB integrity and permeability, application of TTFields at 100 kHz may have the potential to deliver drugs to the brain, which are unable to cross the BBB. Utilizing TTFields to open the BBB and its subsequent recovery could be a clinical approach of drug delivery for treatment of brain tumors and other diseases of the central nervous system. These results will be further validated in clinical Trials.

Effect of sympathetic nerves on cerebral vessels during seizures

1979 ◽  
Vol 237 (2) ◽  
pp. H178-H184 ◽  
Author(s):  
S. M. Mueller ◽  
D. D. Heistad ◽  
M. L. Marcus
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Blood Brain Barrier ◽  
Sympathetic Nerve Activity ◽  
Sympathetic Nerves ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Cervical Sympathetic ◽  
The Brain

The purpose of this study was to determine the effect of activation of sympathetic pathways during seizures on cerebral blood flow and integrity of the blood-brain barrier. We measured cerebral blood flow with microspheres and disruption of the blood-brain barrier with labeled albumin in cats. One cerebral hemisphere was denervated by cutting the superior cervical sympathetic trunk on one side. During bicuculline-induced seizures, superior cervical sympathetic nerve activity increased about threefold. Blood flow to the innervated hemibrain was significantly lower than flow to denervated hemibrain. However, in relation to the total increase in flow, this effect of nerves was minor. Blood-brain barrier permeability increased about sixfold during seizures, but there was no difference between the innervated and denervated sides of the brain. We conclude that sympathetic nerves attenuate the increase in cerebral blood flow during seizures, despite the increase in metabolism, but this effect is small. Activation of sympathetic nerves does not reduce disruption of the blood-brain barrier during seizures.

scholarly journals Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier

2015 ◽  
Vol 7 (284) ◽  
pp. 284ra59-284ra59 ◽  
Author(s):  
Helen M. Lazear ◽  
Brian P. Daniels ◽  
Amelia K. Pinto ◽  
Albert C. Huang ◽  
Sarah C. Vick ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Blood Brain Barrier ◽  
West Nile Virus Infection ◽  
Antiviral Effect ◽  
Brain Barrier ◽  
West Nile ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Brain ◽  
Interferon Λ

Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1−/− mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1−/− mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1−/− mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis– and signal transducer and activator of transcription 1 (STAT1)–independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis.

Selective blood-tumor barrier disruption by leukotrienes

1992 ◽  
Vol 77 (3) ◽  
pp. 407-410 ◽  
Author(s):  
Chung-Ching Chio ◽  
Takehiko Baba ◽  
Keith L. Black
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Barrier Permeability ◽  
Content Type ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Mean ◽  
Fine Print

✓ The authors have previously reported that intracarotid infusion of 5 µg leukotriene C4 (LTC4) selectively increases blood-tumor barrier permeability in rat RG-2 tumors. In this study, rats harboring RG-2 tumors were given 15-minute intracarotid infusions of LTC4 at concentrations ranging from 0.5 µg to 50.0 µg (seven rats in each dose group). Blood-tumor and blood-brain barrier permeability were determined by quantitative autoradiography using 14C aminoisobutyric acid. The transfer constant for permeability (Ki) within the tumors was increased twofold by LTC4 doses of 2.5, 5.0, and 50.0 µg compared to vehicle alone (90.00 ±21.14, 92.68 ± 15.04, and 80.17 ± 16.15 vs. 39.37 ± 6.45 µl/gm/min, respectively; mean ± standard deviation; p < 0.01). No significant change in Ki within the tumors was observed at the 0.5-µg LTC4 dose. Blood-brain barrier permeability was selectively increased within the tumors. At no dose in this study did leukotrienes increase permeability within normal brain. To determine the duration of increased opening of the blood-tumor barrier by LTC4 administration, Ki was measured at 15, 30, and 60 minutes after termination of a 15-minute LTC4 infusion (seven rats at each time point). The mean Ki value was still high at 15 minutes (92.68 ± 15.04 µl/gm/min), but declined at 30 minutes (56.58 ± 12.50 µl/gm/min) and 60 minutes (55.40 ± 8.10 µl/gm/min) after the end of LTC4 infusion. Sulfidopeptide leukotrienes LTC4, LTD4, LTE4 and LTF4 were infused to compare their potency in opening the blood-tumor barrier. The mean leukotriene E4 was the most potent, increasing the permeability value 37½ fold compared with vehicle alone (139.86 ± 23.95 vs. 39.37 ± 6.45 µl/gm/min).

scholarly journals Expression of Neuronal CXCL10 Induced by Rabies Virus Infection Initiates Infiltration of Inflammatory Cells, Production of Chemokines and Cytokines, and Enhancement of Blood-Brain Barrier Permeability

2014 ◽  
Vol 89 (1) ◽  
pp. 870-876 ◽  
Author(s):  
Qingqing Chai ◽  
Ruiping She ◽  
Ying Huang ◽  
Zhen F. Fu
Keyword(s):  
Protein Expression ◽  
Blood Brain Barrier ◽  
Rabies Virus ◽  
Inflammatory Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Rabies Virus Infection ◽  
Ifn Γ ◽  
Bbb Permeability

It has been shown that enhancement of blood-brain barrier (BBB) permeability is modulated by the expression of chemokines/cytokines and reduction of tight junction (TJ) proteins in the brains of mice infected with rabies virus (RABV). Since CXCL10 was found to be the most highly expressed chemokine, its temporal and spatial expression were determined in the present study. The expression of the chemokine CXCL10 was initially detected in neurons as early as 3 days postinfection (p.i.) in the brains of RABV-infected mice, after which it was detected in microglia (6 days p.i.) and astrocytes (9 days p.i.). Neutralization of CXCL10 by treatment with anti-CXCL10 antibodies reduced gamma interferon (IFN-γ) production and Th17 cell infiltration, as well as restoring TJ protein expression and BBB integrity. Together, these data suggest that it is the neuronal CXCL10 that initiates the cascade that leads to the activation of microglia/astrocytes, infiltration of inflammatory cells, expression of chemokines/cytokines, reduction of TJ protein expression, and enhancement of the BBB permeability.

scholarly journals Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

2013 ◽  
Vol 33 (12) ◽  
pp. 1944-1954 ◽  
Author(s):  
Ngoc H On ◽  
Sanjot Savant ◽  
Myron Toews ◽  
Donald W Miller
Keyword(s):  
Drug Delivery ◽  
Molecular Weight ◽  
Blood Brain Barrier ◽  
Lysophosphatidic Acid ◽  
Near Infrared ◽  
Brain Barrier ◽  
Small Molecular Weight ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Brain

The present study characterizes the effects of lysophosphatidic acid (LPA) on blood–brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain.

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