Protection Against Blood-brain Barrier Permeability as a Possible Mechanism for Protective Effects of Thymoquinone Against Sickness Behaviors Induced by Lipopolysaccharide in Rats

Background: Blood-brain barrier (BBB), as well-known protection for the brain, plays an active role in normal homeostasis. It might be changed by a range of inflammatory mediators to have a role in sickness behaviors. Objectives: Regarding the anti-inflammatory effects of thymoquinone (TQ), its protection against BBB permeability, as a possible mechanism for protective effects against sickness behaviors elicited by lipopolysaccharide (LPS), was evaluated in rats. Methods: The animals were grouped as follows and treated (n = 10 in each): (1) control (saline); (2) LPS 1 mg/kg, was injected two hours before behavioral tests for two weeks; (3-5) 2, 5, and 10 mg/kg TQ, respectively was injected 30 min before LPS injection. Open-field (OF), elevated plus-maze (EPM) and Forced Swimming test (FST) were done. Finally, the animals were anesthetized to evaluate for BBB permeability using Evans blue (EB) dye method. Results: Compared with control, LPS decreased the peripheral distance and crossing and also total crossing and distance in OF, (P < 0.01 - P < 0.001). The central crossing and distance and central time in all three treatment groups were more than LPS (P < 0.05 - P < 0.001). LPS also reduced the entries and the time spent in the open arm while increased the time spent in the closed arm in EPM (P < 0.05 - P < 0.001). The effects of LPS were reversed by TQ (P < 0.05 - P < 0.001). In FST, the immobility time and active time were increased and decreased by LPS compared with control (P < 0.001), respectively. In all three TQ-treated groups, the active and climbing times were more while the immobility time was fewer than the LPS (P < 0.05 - P < 0.001). The animals of the LPS group showed more EB dye content in their brain tissue than the control group (P < 0.05 - P < 0.001). TQ significantly reduced EB dye content of the brain tissues (P < 0.05 - P < 0.001). Conclusions: According to this study, protection against BBB permeability as a possible mechanism for the protective effects of TQ against sickness behaviors induced by LPS might be suggested.

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

10.36106/ijsr/6505925 ◽

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

Neuro-Oncology ◽

10.1093/neuonc/noz175.336 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi82-vi82 ◽

Cited By ~ 2

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.

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

Journal of Neurosurgery ◽

10.3171/jns.1982.57.3.0394 ◽

1982 ◽

Vol 57 (3) ◽

pp. 394-398 ◽

Cited By ~ 60

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.154 ◽

2013 ◽

Vol 33 (12) ◽

pp. 1944-1954 ◽

Cited By ~ 30

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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P11.28 Alteration of blood brain barrier (BBB) permeability by Tumor Treating Fields (TTFields) in vivo

Neuro-Oncology ◽

10.1093/neuonc/noz126.174 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii49-iii49

Author(s):

A F Keßler ◽

E Salvador ◽

D Domröse ◽

M Burek ◽

C Tempel Brami ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Dce Mri ◽

Tumor Treating Fields ◽

Blood Brain ◽

Vessel Structure ◽

Bbb Permeability ◽

The Brain

Abstract BACKGROUND Alternating electric fields with intermediate frequency (100 - 300 kHz) and low intensity (1 - 3 V/cm), known as Tumor Treating Fields (TTFields), have been established as a novel adjuvant therapy for glioblastoma (GBM) patients. The blood brain barrier (BBB) tightly controls the influx of the majority of compounds from blood to brain. Due to this regulation, the BBB may block delivery of drugs for treatment of brain tumors, in particular GBM. In this study, we investigated the influence of TTFields on BBB permeability in vivo. MATERIAL AND METHODS For determination of BBB permeability, rats were treated with 100 kHz TTFields for 72 h. At the end of treatment, rats were i.v. injected with Evan′s Blue (EB), which binds Albumin (~70 kDa) upon injection to the blood. EB was extracted after brain homogenization and quantified at 610 nm. In addition, cryosections of rat brains were prepared following TTFields application at 100 kHz for 72 h, and sections were stained for Claudin 5, Occludin and immunoglobulin G (IgG) to assess vessel structure. Moreover, serial dynamic contrast-enhanced DCE-MRI with Gadolinium contrast agent (Gd) was performed before and after TTFields application. RESULTS In vivo, the EB accumulation in the brain was significantly increased by application of TTFields to the rat head. Claudin 5 and Occludin staining was visible in vessel endothelial cells and localized at the cells’ edges in control cryosections of rat brains. In TTFields-treated rats, the vessel structure became diffuse; Claudin 5 and Occludin were delocalized and IgG was found throughout the brain tissue and not solely inside the vessels, as it is normally the case. Serial DCE-MRI demonstrated significantly increased accumulation of Gd in the brain, detected directly after 72 h of TTFields application. 96 h after end of TTFields treatment the effect on the BBB disappeared and no difference in contrast enhancement between controls and TTFields treated animals was observable. CONCLUSION Application of TTFields at 100 kHz could have the potential to deliver drugs to the brain, which normally are unable to cross the BBB by altering BBB integrity and permeability. Utilizing TTFields to open the BBB and its subsequent recovery, as demonstrated by the data presented herein, could lead to a clinical approach of drug delivery for treatment of malignant brain tumors and other diseases of the central nervous system. These results will be further validated in clinical trials.

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Blood-brain Barrier Crossing using Magnetic Stimulated Nanoparticles

10.1101/2021.12.23.472846 ◽

2021 ◽

Author(s):

Jingfan Chen ◽

Muzhaozi Yuan ◽

Caitlin Madison ◽

Shoshana Eitan ◽

Ya Wang

Keyword(s):

Blood Brain Barrier ◽

Pbpk Model ◽

Superparamagnetic Iron Oxide ◽

Brain Barrier ◽

Control Group ◽

Pbpk Models ◽

Blood Brain ◽

The Impact ◽

The Brain

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly(ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.825) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the brain bioavailability under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47 % in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91 % compared to the group without SMF.

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

Journal of Neurosurgery ◽

10.3171/jns.1980.53.5.0666 ◽

1980 ◽

Vol 53 (5) ◽

pp. 666-673 ◽

Cited By ~ 4

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).

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Gestational Hypoxia and Blood-Brain Barrier Permeability: Early Origins of Cerebrovascular Dysfunction Induced by Epigenetic Mechanisms

Frontiers in Physiology ◽

10.3389/fphys.2021.717550 ◽

2021 ◽

Vol 12 ◽

Author(s):

Emilio A. Herrera ◽

Alejandro González-Candia

Keyword(s):

Blood Brain Barrier ◽

Neurovascular Unit ◽

Fetal Brain ◽

Brain Barrier ◽

Normal Brain ◽

Epigenetic Mechanisms ◽

Blood Brain ◽

Intrauterine Hypoxia ◽

Bbb Permeability ◽

The Brain

Fetal chronic hypoxia leads to intrauterine growth restriction (IUGR), which is likely to reduce oxygen delivery to the brain and induce long-term neurological impairments. These indicate a modulatory role for oxygen in cerebrovascular development. During intrauterine hypoxia, the fetal circulation suffers marked adaptations in the fetal cardiac output to maintain oxygen and nutrient delivery to vital organs, known as the “brain-sparing phenotype.” This is a well-characterized response; however, little is known about the postnatal course and outcomes of this fetal cerebrovascular adaptation. In addition, several neurodevelopmental disorders have their origins during gestation. Still, few studies have focused on how intrauterine fetal hypoxia modulates the normal brain development of the blood-brain barrier (BBB) in the IUGR neonate. The BBB is a cellular structure formed by the neurovascular unit (NVU) and is organized by a monolayer of endothelial and mural cells. The BBB regulates the entry of plasma cells and molecules from the systemic circulation to the brain. A highly selective permeability system achieves this through integral membrane proteins in brain endothelial cells. BBB breakdown and dysfunction in cerebrovascular diseases lead to leakage of blood components into the brain parenchyma, contributing to neurological deficits. The fetal brain circulation is particularly susceptible in IUGR and is proposed to be one of the main pathological processes deriving BBB disruption. In the last decade, several epigenetic mechanisms activated by IU hypoxia have been proposed to regulate the postnatal BBB permeability. However, few mechanistic studies about this topic are available, and little evidence shows controversy. Therefore, in this mini-review, we analyze the BBB permeability-associated epigenetic mechanisms in the brain exposed to chronic intrauterine hypoxia.

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Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

Frontiers in Neurology ◽

10.3389/fneur.2020.577312 ◽

2021 ◽

Vol 11 ◽

Author(s):

Damir Janigro ◽

Damian M. Bailey ◽

Sylvain Lehmann ◽

Jerome Badaut ◽

Robin O'Flynn ◽

...

Keyword(s):

Blood Brain Barrier ◽

Peripheral Blood ◽

Neuronal Damage ◽

Neurovascular Unit ◽

Brain Barrier ◽

Traumatic Head Injury ◽

Blood Brain ◽

Gravitational Stress ◽

Bbb Permeability ◽

The Brain

Within the neurovascular unit (NVU), the blood–brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.

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