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

✓ 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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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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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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Hyperosmotic blood-brain barrier disruption in brains of rats with an intracerebrally transplanted RG-C6 tumor

Journal of Neurosurgery ◽

10.3171/jns.1987.66.2.0256 ◽

1987 ◽

Vol 66 (2) ◽

pp. 256-263 ◽

Cited By ~ 33

Author(s):

Tooru Inoue ◽

Masashi Fukui ◽

Shunji Nishio ◽

Katsutoshi Kitamura ◽

Hitoshi Nagara

Keyword(s):

Blood Brain Barrier ◽

Brain Regions ◽

Progressive Increase ◽

Brain Barrier ◽

Blue Dye ◽

Normal Brain ◽

Content Type ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Bbb Opening

✓ To test the results of blood-brain barrier (BBB) disruption in the treatment of brain tumor, RG-C6 glioma was transplanted into the brains of rats. Intracarotid infusions of normal saline and hyperosmotic mannitol were then made, followed by intravenous injection of Evans blue dye plus albumin (EB, MW 68,000), horseradish peroxidase (HRP, MW 40,000), and 5-fluorouracil (5-FU, MW 130). Uptake of the drug and the consistency of drug levels in the normal brain and tumor varied widely among these three agents. Both EB and HRP penetrated the brain tumors but did not stain the normal brain tissues. After BBB opening, penetration of EB and HRP into the normal brain was drastically increased; however, the uptake of EB and HRP in the tumor was not increased. The concentration of 5-FU in the tumor was higher than that in the serum and, although it increased 1.5-fold after BBB opening, the increase was not statistically significant. Conversely, there was a progressive increase in concentrations of 5-FU in the tumor-free brain regions (p < 0.05). These observations suggest that an intracarotid infusion of hyperosmotic mannitol may increase neurotoxicity because it allows greater delivery of anticancer drugs into the normal brain tissue than into the tumor tissues.

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Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8+T Cells with Different Specificities

Infection and Immunity ◽

10.1128/iai.02180-14 ◽

2014 ◽

Vol 82 (11) ◽

pp. 4854-4864 ◽

Cited By ~ 28

Author(s):

Chek Meng Poh ◽

Shanshan W. Howland ◽

Gijsbert M. Grotenbreg ◽

Laurent Rénia

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Blood Brain Barrier ◽

Synergistic Effects ◽

Brain Barrier ◽

High Dose ◽

Experimental Cerebral Malaria ◽

Content Type ◽

Blood Brain

ABSTRACTCD8+T cells play a pathogenic role in the development of murine experimental cerebral malaria (ECM) induced byPlasmodium bergheiANKA (PbA) infection in C57BL/6 mice. Only a limited number of CD8+epitopes have been described. Here, we report the identification of a new epitope from the bergheilysin protein recognized by PbA-specific CD8+T cells. Induction and functionality of these specific CD8+T cells were investigated in parallel with previously reported epitopes, using new tools such as tetramers and reporter cell lines that were developed for this study. We demonstrate that CD8+T cells of diverse specificities induced during PbA infection share many characteristics. They express cytolytic markers (gamma interferon [IFN-γ], granzyme B) and chemokine receptors (CXCR3, CCR5) and damage the blood-brain barrierin vivo. Our earlier finding that brain microvessels in mice infected with PbA, but not with non-ECM-causing strains, cross-presented a shared epitope was generalizable to these additional epitopes. Suppressing the induction of specific CD8+T cells through tolerization with a high-dose peptide injection was unable to confer protection against ECM, suggesting that CD8+T cells of other specificities participate in this process. The tools that we developed can be used to further investigate the heterogeneity of CD8+T cell responses that are involved in ECM.

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Blood-brain barrier permeability in staphylococcal cerebritis and early brain abscess

Journal of Neurosurgery ◽

10.3171/jns.1994.80.5.0897 ◽

1994 ◽

Vol 80 (5) ◽

pp. 897-905 ◽

Cited By ~ 15

Author(s):

Warren D. Lo ◽

Arlene Wolny ◽

Carl Boesel

Keyword(s):

Blood Flow ◽

Brain Edema ◽

Brain Abscess ◽

Blood Brain Barrier ◽

Plasma Volume ◽

Brain Barrier ◽

Content Type ◽

Blood Brain ◽

Bbb Permeability ◽

Fine Print

✓ The pattern of radiographic enhancement in cases of brain abscess has been extensively studied, but the magnitude of blood-brain barrier (BBB) damage that accompanies enhancement has not. The question of whether BBB permeability increases continuously as a cerebritis evolves into an abscess was studied. The tracers 3H-labeled aminoisobutyric acid and 14C-labeled butanol were used in a rat Staphylococcus aureus cerebritis model to measure simultaneously BBB permeability and blood flow. The rats were examined at 1, 2, 3, 5, or 7 days after inoculation, and tissue samples were collected from the cerebritis site and uninoculated regions. Permeability of the BBB in the cerebritis region increased to five times the normal values by 72 hours after inoculation, then reached a plateau. The plasma volume in the cerebritis region increased to six times greater than the normal value at 72 hours, then remained unchanged. Uninoculated brain in both ipsilateral and contralateral hemispheres showed no significant changes. Cerebral blood flow was not substantially altered at the inoculated or uninoculated sites. In this model, incidence of BBB damage rises rapidly, reaches a plateau, and does not continue to increase despite the ongoing evolution of a cerebritis into an abscess. The BBB damage is accompanied by an increase in the regional plasma volume, a novel finding that has not been previously reported in central nervous system inflammation. These results suggest that the vascular events contributing to brain edema formation become established early in the cerebritis phase and imply that control of the host's inflammatory response is important in the management of cerebritis-associated brain edema.

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The effect of steroids on gentamicin delivery to brain after blood-brain barrier disruption

Journal of Neurosurgery ◽

10.3171/jns.1990.72.1.0123 ◽

1990 ◽

Vol 72 (1) ◽

pp. 123-126 ◽

Cited By ~ 6

Author(s):

Edward A. Neuwelt ◽

Alfred Horaczek ◽

Michael A. Pagel

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Structural Damage ◽

Vasogenic Edema ◽

Brain Barrier ◽

Normal Brain ◽

Content Type ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Wide Range

✓ Osmotic modification of the blood-brain barrier (BBB) provides an experimental model of vasogenic edema, is totally reversible, and does not cause any structural damage. In the present communication, the effect of corticosteroids on drug delivery to normal rat brain was evaluated in this model. Intraperitoneal dexamethasone was administered at doses ranging from 12 to 48 mg/sq m for 3 days; gentamicin delivery to the brain was then evaluated after either intravenous or intracarotid administration in both control and BBB-modified animals. Only animals receiving the highest dose of dexamethasone and in which the gentamicin was given intravenously demonstrated a statistically significant decrease in drug delivery. The effect of dexamethasone over a wide range of dosages, therefore, exhibited only modest effects on drug delivery to normal brain after osmotic BBB disruption.

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The Role and Mechanism of Borneol to Open the Blood-Brain Barrier

Integrative Cancer Therapies ◽

10.1177/1534735418767553 ◽

2018 ◽

Vol 17 (3) ◽

pp. 806-812 ◽

Cited By ~ 7

Author(s):

Tao Wu ◽

Aiqin Zhang ◽

Hongyang Lu ◽

Qiaoyuan Cheng

Keyword(s):

Blood Brain Barrier ◽

Evans Blue ◽

Corn Oil ◽

Malignant Tumors ◽

Brain Barrier ◽

Control Group ◽

High Dose ◽

Total Density ◽

Sd Rats ◽

Blood Brain

Background: The blood-brain barrier (BBB) is the greatest challenge in the treatment of intracranial malignant tumors. Objective: The aim of this study is to determine the role of borneol in opening the BBB and elucidate the underlying mechanisms. Materials and Methods: Twenty Sprague-Dawley (SD) rats were randomized into borneol group intragastrically administered with 10% borneol corn oil (2 mL/kg) and control group. After 30 minutes, 2% Evans blue (4 mL/kg) was injected. Thirty minutes later, brain tissue was analyzed using the Evans blue standard curve. Another 40 SD rats were randomized into high-, medium-, and low-dose borneol groups and a control group. Each rat in the experimental groups was intragastrically administered with 10% borneol corn oil (2 mL/kg, 1.25 mL/kg, and 0.5 mL/kg, respectively). The control group was injected with corn oil of 1.25 mL/kg. After 30 minutes, the rats were killed, and the brain tissues were collected. The expression of occludin, occludens-1, nitric oxide synthase, P-glycoprotein, and intercellular cell adhesion molecule-1 (ICAM-1) was detected by immunohistochemy. Results: The concentration of Evans blue in the borneol group was higher than in the control group ( P < .05). The mean density of ICAM-1 expression was higher in the experimental group than in the control group ( P < .05). In contrast, significant differences of positive area and total density of ICAM-1 were shown only between the high-dose group and the control group ( P < .05). Conclusion: Borneol can open the BBB, which might be related with the increased expression of ICAM-1.

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