Cerebrovascular Permeability in the Normal Brain and Following Osmotic Opening of the Blood-Brain Barrier

Systemic administration of luteinizing hormone-releasing hormone (LHRH) in rats has been found to influence behavior independently of pituitary or ovarian function. A previous study has shown that LHRH can cross the blood-brain barrier in one direction, but it was not known whether this was due to a saturable transport system. The rate of entry of 125I-labeled LHRH from blood to brain was determined by two different single-pass methods of carotid perfusion. The first, a multiple time point method, measures Ki from the slope of the linear regression when brain-to-blood ratios of radioiodinated LHRH are plotted against time. Saturable transport was determined by the difference between the Ki of rats perfused with 125I-LHRH (12.51 X 10(-3) mg.g-1.min-1) vs. rats perfused with 125I-LHRH and unlabeled LHRH (10 nmol/ml; 2.20 X 10(-3) ml.g-1.min-1). The inhibition by the unlabeled peptide was statistically significant (P less than 0.001). The second method, a single time point technique, measures the cerebrovascular permeability-surface area coefficient (PA). Saturable transport was determined in rats by the competition of unlabeled LHRH with 125I-LHRH. The PA value for 125I-LHRH (20.00 X 10(-3) ml.g-1.min-1) was significantly greater (P less than 0.05) than for 125I-LHRH with the addition of 10 nmol/ml unlabeled LHRH (4.14 X 10(-3) ml.g-1.min-1). Saturable transport of LHRH from brain to blood in mice was also determined.(ABSTRACT TRUNCATED AT 250 WORDS)

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Blood-Brain Barrier and Exercise – a Short Review

Journal of Human Kinetics ◽

10.2478/v10078-008-0006-x ◽

2008 ◽

Vol 19 (1) ◽

pp. 83-92 ◽

Cited By ~ 4

Author(s):

Katarzyna Nierwińska ◽

Elżbieta Malecka ◽

Małgorzata Chalimoniuk ◽

Aleksandra Żebrowska ◽

Józef Langfort

Keyword(s):

Blood Brain Barrier ◽

Brain Injuries ◽

Marked Change ◽

Short Review ◽

Brain Barrier ◽

Neural Function ◽

Normal Brain ◽

Cns Injury ◽

Blood Brain ◽

Bbb Permeability

Blood-Brain Barrier and Exercise – a Short ReviewBlood-brain barier (BBB) segregates central nervous system (CNS) from the circulating blood. BBB is formed by the brain capillary endothelial cells with complex tight junctions between them as well as by astrocytes and pericytes. BBB is responsible for transport of selected chemicals into and out of the CNS as well as for its protection from fluctuations in plasma composition following meals, during exercise and from circulating agents such as neurotransmitters, xenobiotics and other potentially harmful substances capable to disturb neural function. BBB may be compromised during CNS injury, infection, fever and in some nerodegenerative diseases. The increase of BBB permeability was observed also during exercise as documented by changes of plasma S-100 protein levels, used as a peripheral marker of BBB integrity. Marked change in BBB integrity during exercise may disturb normal brain function and contribute to the development of central fatigue. Moreover, serum S-100β may indicate level of injury in individuals suffering brain injuries during sports. There are also data suggesting that acute effect of physical exercise on serum S100β levels may not be related with CNS injury. Further studies to establish whether training and which type of it may modulate BBB permeability are needed.

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Quantification and pharmacokinetics of blood-brain barrier disruption in humans

Journal of Neurosurgery ◽

10.3171/jns.1996.85.6.1056 ◽

1996 ◽

Vol 85 (6) ◽

pp. 1056-1065 ◽

Cited By ~ 73

Author(s):

Bernhard Zünkeler ◽

Richard E. Carson ◽

Jeff Olson ◽

Ronald G. Blasberg ◽

Hetty Devroom ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Normal Brain ◽

Content Type ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption ◽

Fine Print

✓ Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 ± 1.4 and 34.1 ± 22.1 µl/minute/ml (± standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 ± 11.7 and 19.7 ± 10.7 µl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 ± 3.8 and 4.2 ± 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 µM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

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Selective blood-tumor barrier disruption by leukotrienes

Journal of Neurosurgery ◽

10.3171/jns.1992.77.3.0407 ◽

1992 ◽

Vol 77 (3) ◽

pp. 407-410 ◽

Cited By ~ 46

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).

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Intracarotid Infusion of Leukotriene C4 Selectively Increases Blood-Brain Barrier Permeability after Focal Ischemia in Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1991.115 ◽

1991 ◽

Vol 11 (4) ◽

pp. 638-643 ◽

Cited By ~ 71

Author(s):

Takehiko Baba ◽

Keith L. Black ◽

Kiyonobu Ikezaki ◽

Kangnian Chen ◽

Donald P. Becker

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Normal Brain ◽

Brain Capillaries ◽

Transfer Constant ◽

Blood Brain ◽

Mca Occlusion ◽

Ischemic Tissue ◽

Bbb Permeability ◽

Glutamyl Transpeptidase

Intracarotid infusions of leukotriene C4 (LTC4) were used to open selectively the blood–brain barrier (BBB) in ischemic tissue after middle cerebral artery (MCA) occlusion in rats. BBB permeability was determined by quantitative autoradiography using [14C]aminoisobutyric acid. Seventy-two hours after MCA occlusion, LTC4 (4 μg total dose) infused into the carotid artery ipsilateral to the MCA occlusion selectively increased the unidirectional transfer constant for permeability K1 approximately threefold within core ischemic tissue and tissue adjacent to the ischemic core. No effect on BBB permeability was seen within nonischemic brain tissue or in ischemic tissue after only 24 h after MCA occlusion. γ-Glutamyl transpeptidase (γ-GTP) activity was decreased in capillaries in ischemic tissue at 48 and 72 h after infarction, compared to high γ-GTP in normal brain capillaries and moderate γ-GTP in capillaries in the ischemic tissue at 24 h after infarction. These findings suggest that normal brain capillaries resist the vasogenic effects of LTC4. In contrast, LTC4 increases permeability in capillaries of ischemic tissue, where γ-GTP is decreased. γ-Glutamyl transpeptidase, an enzyme that inactivates LTC4 to LTD4 and LTE4 to LTF4, may act as an “enzymatic barrier” in normal brain capillaries to leukotrienes.

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The effect of interleukin-2 on the blood-brain barrier in the 9L gliosarcoma rat model

Journal of Neurosurgery ◽

10.3171/jns.1989.70.1.0092 ◽

1989 ◽

Vol 70 (1) ◽

pp. 92-96 ◽

Cited By ~ 16

Author(s):

Joseph T. Alexander ◽

Stephen C. Saris ◽

Edward H. Oldfield

Keyword(s):

Blood Brain Barrier ◽

Interleukin 2 ◽

Brain Barrier ◽

High Dose ◽

Normal Brain ◽

Content Type ◽

Tumor Bearing ◽

Blood Brain ◽

Significant Difference ◽

Fine Print

✓ Carbon-14-labeled aminoisobutyric acid was used to determine local blood-to-tissue transfer constants in 22 Fischer rats with intracerebral 9L gliosarcomas that received either high-dose parenteral interleukin-2 (IL-2) or a control injection. In tumor and peritumoral tissue, the transfer constants in the IL-2-treated animals (89.6 ± 14.6 and 35.8 ± 6.0, respectively, mean ± standard error of the mean) were larger (p < 0.05) than in control animals (61.4 ± 6.4 and 14.6 ± 2.2, respectively). In contrast, in normal frontal and occipital tissue contralateral to the tumor-bearing hemisphere, there was no significant difference between the transfer constants in IL-2-treated and control animals. Furthermore, treatment of animals with IL-2 excipient caused no change in permeability as compared to animals treated with Hanks' balanced salt solution. Parenteral injection of IL-2 increases blood-brain barrier disruption in tumor-bearing rat brain but does not increase the vascular permeability of normal brain. Methods to prevent this increased tumor vessel permeability are required before parenteral IL-2 can be used safely for the treatment of primary or metastatic brain tumors.

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Gene Expression Changes in Long-Term In Vitro Human Blood-Brain Barrier Models and Their Dependence on a Transwell Scaffold Material

Journal of Healthcare Engineering ◽

10.1155/2017/5740975 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Joel D. Gaston ◽

Lauren L. Bischel ◽

Lisa A. Fitzgerald ◽

Kathleen D. Cusick ◽

Bradley R. Ringeisen ◽

...

Keyword(s):

Gene Expression ◽

Blood Brain Barrier ◽

Disease Modeling ◽

Brain Barrier ◽

Cell Contact ◽

Normal Brain ◽

Scaffold Material ◽

Blood Brain ◽

Coculture Model

Disruption of the blood-brain barrier (BBB) is the hallmark of many neurovascular disorders, making it a critically important focus for therapeutic options. However, testing the effects of either drugs or pathological agents is difficult due to the potentially damaging consequences of altering the normal brain microenvironment. Recently, in vitro coculture tissue models have been developed as an alternative to animal testing. Despite low cost, these platforms use synthetic scaffolds which prevent normal barrier architecture, cellular crosstalk, and tissue remodeling. We created a biodegradable electrospun gelatin mat “biopaper” (BP) as a scaffold material for an endothelial/astrocyte coculture model allowing cell-cell contact and crosstalk. To compare the BP and traditional models, we investigated the expression of 27 genes involved in BBB permeability, cellular function, and endothelial junctions at different time points. Gene expression levels demonstrated higher expression of transcripts involved in endothelial junction formation, including TJP2 and CDH5, in the BP model. The traditional model had higher expression of genes associated with extracellular matrix-associated proteins, including SPARC and COL4A1. Overall, the results demonstrate that the BP coculture model is more representative of a healthy BBB state, though both models have advantages that may be useful in disease modeling.

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Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain?

Stem Cells International ◽

10.1155/2020/8889061 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yvonne Cashinn Chia ◽

Clarice Evey Anjum ◽

Hui Rong Yee ◽

Yenny Kenisi ◽

Mike K. S. Chan ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

Blood Brain Barrier ◽

Cellular Therapy ◽

Immune Cell ◽

Brain Barrier ◽

Normal Brain ◽

Brain Functions ◽

Blood Brain ◽

The Brain

Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.

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Cerebrovascular permeability and delivery of gentamicin to normal brain and experimental brain abscess in rats

Journal of Neurosurgery ◽

10.3171/jns.1984.61.3.0430 ◽

1984 ◽

Vol 61 (3) ◽

pp. 430-439 ◽

Cited By ~ 27

Author(s):

Edward A. Neuwelt ◽

David E. Baker ◽

Michael A. Pagel ◽

Nathan K. Blank

Keyword(s):

Brain Abscess ◽

Blood Brain Barrier ◽

Medical Management ◽

Brain Barrier ◽

High Dose ◽

Normal Brain ◽

Content Type ◽

Stage Of Development ◽

Blood Brain ◽

Brain Abscesses

✓ Antibiotics vary widely in their ability to penetrate the blood-brain barrier. In studies of 70 rats, the permeability of the normal blood-brain barrier to gentamicin was shown to be poor. In experimental brain abscesses, during the cerebritic stage of development, the penetration of intravenous antibiotics was increased compared to normal brain but was very inconsistent. Antibiotic delivery to brain abscess was not significantly altered with the administration of high-dose steroids, but the macrophage and glial response was markedly decreased with high-dose steroid therapy. Reversible osmotic blood-brain barrier modification with mannitol increased the delivery of gentamicin both to brain abscess and to the surrounding brain. It also resulted in more consistent tissue drug levels. The clinical implications of these studies suggest that, because of the inconsistent delivery of gentamicin to brain abscess, the therapeutic efficacy of medical management alone may be quite variable. This mode of therapy could possibly increase the efficacy of medical management of brain abscesses, especially in patients with multiple or surgically inaccessible brain abscesses.

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Current Non-Viral Gene Therapy Strategies for the Treatment of Glioblastoma

Current Medicinal Chemistry ◽

10.2174/0929867328666210525141243 ◽

2021 ◽

Vol 28 ◽

Author(s):

Antonela Sofía Asad ◽

Alejandro Javier Nicola Candia ◽

Nazareno González ◽

Camila Florencia Zuccato ◽

Adriana Seilicovich ◽

...

Keyword(s):

Gene Therapy ◽

Blood Brain Barrier ◽

Viral Vectors ◽

Malignant Gliomas ◽

Brain Parenchyma ◽

Brain Barrier ◽

Viral Gene ◽

Normal Brain ◽

Blood Brain ◽

Transgene Delivery

Background: Glioblastoma constitutes the most frequent and aggressive primary malignant brain tumor in adults. Despite the advances in its treatment, its prognosis remains very poor. Gene therapy has been proposed as a complementary treatment, since it may overcome the problem of the blood-brain barrier for systemic therapies, allowing to target tumor cells and their tumor microenvironment locally, without affecting the normal brain parenchyma. In comparison with viral vectors, non-viral vectors became an attractive tool due to their reduced potential of biosafety risks, lower cost, higher availability and easy storage. Objective: In this article, we aimed to outline the current preclinical and clinical developments of non-viral delivery systems for therapeutic transgene delivery in malignant gliomas. Conclusion: Non-viral vectors are efficient tools for gene delivery since they exhibit reduced non-specific cytotoxicity and can go through several modifications in order to achieve high tumor tropism and the ability to cross the blood-brain barrier to access the tumor mass. However, further evaluations in preclinical models and clinical trials are required in order to translate it into the neuro-oncology clinic.

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