scholarly journals Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

2016 ◽  
Vol 124 (6) ◽  
pp. 1602-1610 ◽  
Author(s):  
Kevin Beccaria ◽  
Michael Canney ◽  
Lauriane Goldwirt ◽  
Christine Fernandez ◽  
Julie Piquet ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ultrasound Contrast Agent ◽  
Ultra Performance Liquid Chromatography ◽  
Brain Barrier ◽  
Control Group ◽  
Tumor Treatment ◽  
Blood Brain ◽  
Ultrasound Sonication ◽  
Bbb Opening

OBJECT The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumor treatment efficacy. The effect of ultrasound-induced BBB opening on the intracerebral concentration of temozolomide (TMZ) and irinotecan (CPT-11) was assessed. METHODS This study was performed using 34 healthy New Zealand rabbits. Half had unilateral BBB opening, and half served as controls. Sonications were performed by pulsing a 1.05-MHz planar ultrasound transducer with a duty cycle of 2.5% and an in situ acoustic pressure level of 0.6 MPa after injection of a microbubble ultrasound contrast agent. Drugs were injected either 5 minutes before (ChemoPreUS) or 15 minutes after (ChemoPostUS) the ultrasound sonication. The plasma and intracerebral concentrations of both drugs were quantified using ultra-performance liquid chromatography. RESULTS The mean intracerebral tissue-to-plasma drug concentration ratio in the control hemispheres was 34% for TMZ and 2% for CPT-11. After BBB opening, these values increased by up to 21% for TMZ and up to 178% for CPT-11. Intracerebral concentrations of drugs were enhanced in regions where the BBB was opened compared with the contralateral hemisphere (p < 0.01 and p < 0.0001 for CPT-11, p = 0.02 and p = 0.03 for TMZ, in ChemoPreUS and ChemoPostUS, respectively) and compared with the control group (p < 0.001 and p < 0.0001 for CPT-11, p < 0.01 and p = 0.02 for TMZ, in ChemoPreUS and ChemoPostUS, respectively). The intracerebral distribution of drugs was heterogeneous, depending on the distance from the ultrasound source. CONCLUSIONS Ultrasound-induced opening of the BBB significantly enhances the intracerebral concentration of both TMZ and CPT-11 in rabbits.

Opening of the blood-brain barrier with an unfocused ultrasound device in rabbits

2013 ◽  
Vol 119 (4) ◽  
pp. 887-898 ◽  
Author(s):  
Kevin Beccaria ◽  
Michael Canney ◽  
Lauriane Goldwirt ◽  
Christine Fernandez ◽  
Clovis Adam ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Blood Brain Barrier ◽  
Ultrasonic Transducer ◽  
Brain Barrier ◽  
Single Element ◽  
Blood Brain ◽  
The Us ◽  
The Brain ◽  
Bbb Opening

Object The blood-brain barrier (BBB) is a major impediment to the intracerebral diffusion of drugs used in the treatment of gliomas. Previous studies have demonstrated that pulsed focused ultrasound (US) in conjunction with a microbubble contrast agent can be used to open the BBB. To apply the US-induced opening of the BBB in clinical practice, the authors designed an innovative unfocused US device that can be implanted in the skull and used to transiently and repeatedly open the BBB during a standard chemotherapy protocol. The goal of this preliminary work was to study the opening of the BBB induced by the authors' small unfocused US transducer and to evaluate the effects of the sonications on brain parenchyma. Methods Craniectomy was performed in 16 healthy New Zealand White rabbits; epidural application of a single-element planar ultrasonic transducer operating at 1 MHz was then used with a pulse-repetition frequency of 1 Hz, pulse lengths of 10–35 msec, in situ acoustic pressure levels of 0.3–0.8 MPa, and sonication for 60–120 seconds. SonoVue was intravenously injected during the US applications, and opening of the BBB was determined by detecting extravasation of Evans blue dye (EBD) in brain tissues, quantitative measurement of EBD with UV-visible spectrophotometry, and contrast enhancement after Gd injection in 4.7-T MRI. A histological study was performed to determine adverse effects. Results An opening of the BBB was observed over a large extent of the US beam in the brain corresponding to in situ pressures of greater than 0.2 MPa. The BBB opening observed was highly significant for both EBD (p < 0.01) and MRI Gd enhancement (p < 0.0001). The BBB opening was associated with minor adverse effects that included perivascular red blood cell extravasations that were less than 150 μm in size and not visible on MR images. Moderate edema was visible on FLAIR sequences and limited to the extent of the sonication field. Conclusions The results demonstrate that the BBB can be opened in large areas of the brain in rabbits with lowpower, pulsed, and unfocused US with limited damage to healthy tissue.

Influence of respiratory stress and hypertension upon the blood-brain barrier

1980 ◽  
Vol 53 (5) ◽  
pp. 666-673 ◽  
Author(s):  
Joe Sam Robinson ◽  
Robert A. Moody
Keyword(s):  
Blood Brain Barrier ◽  
Blood Gases ◽  
Brain Barrier ◽  
Control Group ◽  
Arterial Blood Gases ◽  
White Rats ◽  
Arterial Blood ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Bbb Opening

✓ The effects of acute hypertension and respiratory stress induced by Aramine (metaraminol bitartrate) upon blood-brain barrier (BBB) permeability to horseradish peroxidase (HRP) were studied in adult inbred white rats. The BBB permeability was quantitated by slicing the brain of each animal into 500-µ thick sections, incubating the sections using the Reese-Karnovsky method, and counting all observed HRP perivascular exudates. No evidence of BBB compromise or significant elevation of blood pressure (BP) was observed in the following experimental groups: 1) control group of five animals; 2) hyperventilated group of five animals (final mean arterial blood gases: pO2, 104.2 mm Hg; pCO2, 24.8 mm Hg; pH, 7.53); 3) anoxicstress group of five animals (final mean arterial blood gases: pCO2, 31.4 mm Hg; pCO2, 58.2 mm Hg; pH, 7.21). However, in a group of 15 animals subjected to anoxic stress followed by hyperventilation, in addition to extreme changes in the levels of arterial blood gases, a significant BP increase occurred (mean BP increase per second, 3.43 ± 0.25 mm Hg; final mean BP, 163.3 ± 3.18 mm Hg); as well as significant BBB opening (mean number of HRP exudates per animal, 12.2 ± 0.85). Likewise, a final group of 10 animals given intravenous Aramine displayed a significant systemic BP elevation (mean BP increase per second, 6.9 ± 0.38 mm Hg; final mean BP, 165.8 ± 3.16 mm Hg), accompanied by BBB opening (mean number of exudates per animal, 51.5 ± 5.95). The variable most strongly associated with the degree of barrier opening was the rate of BP rise (correlation coefficient = + 0.84).

scholarly journals Dynamic Study of Blood–Brain Barrier Closure after its Disruption using Ultrasound: A Quantitative Analysis

2012 ◽  
Vol 32 (10) ◽  
pp. 1948-1958 ◽  
Author(s):  
Benjamin Marty ◽  
Benoit Larrat ◽  
Maxime Van Landeghem ◽  
Caroline Robic ◽  
Philippe Robert ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Focal Point ◽  
Molecular Size ◽  
Brain Barrier ◽  
Hydrodynamic Diameter ◽  
Power Ultrasound ◽  
Blood Brain ◽  
Ultrasound Sonication ◽  
The Brain ◽  
Bbb Opening

Delivery of therapeutic or diagnostic agents to the brain is majorly hindered by the blood–brain barrier (BBB). Recently, many studies have demonstrated local and transient disruption of the BBB using low power ultrasound sonication combined with intravascular microbubbles. However, BBB opening and closure mechanisms are poorly understood, especially the maximum gap that may be safely generated between endothelial cells and the duration of opening of the BBB. Here, we studied BBB opening and closure under magnetic resonance (MR) guidance in a rat model. First, MR contrast agents (CA) of different hydrodynamic diameters (1 to 65 nm) were employed to estimate the largest molecular size permissible across the cerebral tissues. Second, to estimate the duration of the BBB opening, the CA were injected at various times post-BBB disruption (12 minutes to 24 hours). A T1 mapping strategy was developed to assess CA concentration at the ultrasound (US) focal point. Based on our experimental data and BBB closure modeling, a calibration curve was obtained to compute the half closure time as a function of CA hydrodynamic diameter. These findings and the model provide an invaluable basis for optimal design and delivery of nanoparticles to the brain.

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

2018 ◽  
Vol 17 (3) ◽  
pp. 806-812 ◽  
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.

scholarly journals The Effect of Bile Salts on the Permeability and Ultrastructure of the Perfused, Energy-Depleted, Rat Blood-Brain Barrier

1991 ◽  
Vol 11 (4) ◽  
pp. 644-654 ◽  
Author(s):  
J. Greenwood ◽  
J. Adu ◽  
A. J. Davey ◽  
N. J. Abbott ◽  
M. W. B. Bradbury
Keyword(s):  
Blood Brain Barrier ◽  
Bile Salts ◽  
Structural Changes ◽  
Sodium Deoxycholate ◽  
Ringer Solution ◽  
Brain Barrier ◽  
Rat Blood ◽  
Blood Brain ◽  
Ultrastructural Damage

The action of bile salts upon the rat blood–brain barrier (BBB) was assessed in the absence of energy-yielding metabolism. Brains were perfused in situ with a Ringer solution for 5 min followed by a 1 min perfusion containing either sodium deoxycholate (DOC), taurochenodeoxycholate (TCDC), or Ringer/DNP. The integrity of the BBB was then determined by perfusing with the radiotracer [14C]mannitol for 2.5 min. Alternatively, the brains were perfusion fixed for ultrastructural assessment. At 0.2 m M DOC, the BBB remained intact and the cerebral ultrastructure was similar to the controls. At 1 m M and above, disruption of the BBB became evident. At 2 m M, the cerebral cortex became severely vacuolated, with damaged endothelium and collapsed capillaries. With TCDC, BBB disruption occurred at 0.2 m M without any apparent ultrastructural damage to the micro vasculature. Following 2 m M TCDC, similar, but less widespread, structural changes to the 2 m M DOC-perfused animals was apparent. Opening of the BBB occurred at a concentration lower than that required to cause lysis of either red blood cells or cultured cerebral endothelial cells. It is proposed that the effect of bile salts at concentrations of 1.5 m M and above is largely due to their lytic action as strong detergents on endothelial cell membranes, but that at lower concentrations a more subtle modification of the BBB occurs.

scholarly journals Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Antonios N. Pouliopoulos ◽  
Nancy Kwon ◽  
Greg Jensen ◽  
Anna Meaney ◽  
Yusuke Niimi ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Safety Profile ◽  
Focused Ultrasound ◽  
Multiple Case Study ◽  
Brain Barrier ◽  
Non Invasive ◽  
Blood Brain ◽  
Multiple Case ◽  
Bbb Opening

AbstractAn emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.

IMMUNOHISTOCHEMICAL STUDIES OF BLOOD BRAIN BARRIER AFTER ADMINISTRATION OF ABHRAK BHASM IN WISTAR RATS

2021 ◽  
pp. 13-19
Author(s):  
Amita Singh ◽  
Raj Kumar ◽  
S. K. Kannaujia ◽  
Manikrishna Manikrishna ◽  
N. P. Singh
Keyword(s):  
Blood Brain Barrier ◽  
Wistar Rats ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Major Constituent ◽  
Control Group ◽  
Blood Brain ◽  
Biological Studies ◽  
Immunohistochemical Studies ◽  
The Brain

Abhrak bhasma (AB) is a type of bhasma prepared from repeated incineration of mineral mica with decoctions of about 72 herbs. The particle size of Abhrak bhasm has been shown to be in the range of 29-88 nanometers and Fe, Ca, Si, Mg and K are found to be as major constituent. Many drugs developed to treat Central Nervous System (CNS) disorders are unable to reach the brain parenchyma in therapeutically relevant concentrations. The blood brain barrier protects brain parenchyma from the uctuation of plasma composition, from pathogenic agents and maintains homeostasis of the brain parenchyma by restricting non-specic ux of ions, peptides, proteins and even cells into and out the brain. Immunohistochemistry is being widely employed as a tool for biological studies. This study is conducted to examine the change in the continuity of Blood brain barrier by using immunohistochemistry, once Abhrak bhasm drug is given in experimental animal and also to examine the histology of organs. In this study a total of 30 adult albino Wistar rats of approximately 4 months age (approx. 150-200 gms) of either sex selected randomly to see the effect of Abhrak bhasm, an ayurvedic drug on Wistar rats. The rats were weighed, marked and divided into 5 groups each consisting of six animals. In normal control group (Group E), no drug was administered and in rest of the four treated groups (Group-A,B,C,D), Abhrak bhasm @ 36 mg/kg B.wt. was administered orally once in each rat. Brain, liver, kidneys,spleen and blood samples were collected in 10% formalin solution after euthanizing the rats at 0.5,2,6 & 12 hours of Abhrak bhasma drug intervention. The alterations in any of the biochemical parameters are within the tolerable limits of liver and kidney since the dose of abhrak bhasm did not affect liver and kidneys. In the present study, the increase in ALP level may be the result of alterations in metabolisms that occurred without any signicant alteration in histology of liver. After applying the immunohistochemistry with the research markers GFAP, CD 34, S 100, GLUT-1 and RECA-1 on the rats in groups A,B,C and D, there was no change in the intensity of immunohistochemistry, with respect to control. While on applying the Occludin, the intensity of immunohistochemistry was reduced in all the treatment groups as compared to the control group. On the basis of ndings of present study it can be concluded that the therapeutic dose of Abhrak bhasma causes changes at the level of tight junctions present in blood brain barrier in rats which is shown by immunohistochemistry with occludin research marker. There is no toxic effect of drug on different organs of rats as no signicant changes in histology of organs are seen. More studies need to be done to check the permeability of blood brain barrier for Abhrak bhasma drug, like calculating its concentration in brain tissues and other vital organs of rat.

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