scholarly journals The Blood–Brain Barrier Creatine Transporter is a Major Pathway for Supplying Creatine to the Brain

2002 ◽  
Vol 22 (11) ◽  
pp. 1327-1335 ◽  
Author(s):  
Sumio Ohtsuki ◽  
Masanori Tachikawa ◽  
Hitomi Takanaga ◽  
Hidemi Shimizu ◽  
Masahiko Watanabe ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Brain Barrier ◽  
Major Pathway ◽  
Creatine Transporter ◽  
Blood Brain ◽  
Creatine Uptake ◽  
Capillary Endothelial Cells ◽  
The Brain

Although creatine plays a pivotal role in the storage of phosphate-bound energy in the brain, the source of cerebral creatine is still unclear. The authors examined the contribution made by the creatine transporter (CRT) at the blood–brain barrier in supplying creatine to the brain from blood. An in vivo intravenous administration study suggested that creatine is continuously transported from the blood to the brain against the creatine concentration gradient that exists between brain and blood. Conditionally immortalized mouse brain capillary endothelial cells (TM-BBB) exhibited creatine uptake, which is Na+ and Cl− dependent and inhibited by CRT inhibitors, such as β-guanidinopropionate and guanidinoacetate. Northern blot and immunoblot analyses demonstrated that CRT is expressed in TM-BBB cells and isolated mouse brain microvessels. Moreover, high expression of CRT was observed in the mouse brain capillaries by confocal immunofluorescent microscopy. These results suggest that CRT plays an important role in supplying creatine to the brain via the blood–brain barrier.

The Blood???Brain Barrier Creatine Transporter Is a Major Pathway for Supplying Creatine to the Brain

2002 ◽  
pp. 1327-1335 ◽  
Author(s):  
Sumio Ohtsuki ◽  
Masanori Tachikawa ◽  
Hitomi Takanaga ◽  
Hidemi Shimizu ◽  
Masahiko Watanabe ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Major Pathway ◽  
Creatine Transporter ◽  
Blood Brain ◽  
The Brain

scholarly journals Imaging Brain Amyloid of Alzheimer Disease in Vivo in Transgenic Mice with an Aβ Peptide Radiopharmaceutical

2002 ◽  
Vol 22 (2) ◽  
pp. 223-231 ◽  
Author(s):  
Hwa Jeong Lee ◽  
Yun Zhang ◽  
Chunni Zhu ◽  
Karen Duff ◽  
William M. Pardridge
Keyword(s):  
Alzheimer Disease ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Brain Barrier ◽  
Blood Brain ◽  
Aβ Amyloid ◽  
The Brain

Aβ1–40 is a potential peptide radiopharmaceutical that could be used to image the brain Aβ amyloid of Alzheimer disease in vivo, should this peptide be made transportable through the blood–brain barrier in vivo. The blood–brain barrier transport of [125I]-Aβ1–40 in a transgenic mouse model was enabled by conjugation to the rat 8D3 monoclonal antibody to the mouse transferrin receptor. The Aβ1–40–8D3 conjugate is a bifunctional molecule that binds the blood–brain barrier TfR and undergoes transport into brain and binds the Aβ amyloid plaques of Alzheimer disease. App SW/ Psen1 double-transgenic and littermate control mice were administered either unconjugated Aβ1–40 or the Aβ1–40–8D3 conjugate intravenously, and brain scans were obtained 6 hours later. Immunocytochemical analysis showed abundant Aβ immunoreactive plaques in the brains of the App SW/ Psen1 transgenic mice and there was a selective retention of radioactivity in the brains of these mice at 6 hours after intravenous administration of the conjugate. In contrast, there was no selective sequestration either of the conjugate in control littermate mouse brain or of unconjugated Aβ1–40 in transgenic mouse brain. In conclusion, the results show that it is possible to image the Aβ amyloid burden in the brain in vivo with an amyloid imaging agent, provided the molecule is conjugated to a blood–brain barrier drug-targeting system.

scholarly journals The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1833
Author(s):  
Shannon Morgan McCabe ◽  
Ningning Zhao
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Blood Circulation ◽  
Critical Role ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

Refining In Vitro Neurotoxicity Testing — The Development of Blood–Brain Barrier Models

2003 ◽  
Vol 31 (3) ◽  
pp. 273-276 ◽  
Author(s):  
Hanna Tähti ◽  
Heidi Nevala ◽  
Tarja Toimela
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Culture Methods ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model

The purpose of this paper is to review the current state of development of advanced in vitro blood–brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.

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.

scholarly journals Permeability of the windows of the brain: feasibility of dynamic contrast-enhanced MRI of the circumventricular organs

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Inge C. M. Verheggen ◽  
Joost J. A. de Jong ◽  
Martin P. J. van Boxtel ◽  
Alida A. Postma ◽  
Frans R. J. Verhey ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Gray Matter ◽  
Circumventricular Organs ◽  
Brain Barrier ◽  
Dce Mri ◽  
Dynamic Contrast Enhanced ◽  
Blood Brain ◽  
Contrast Enhanced ◽  
The Brain

Abstract Background Circumventricular organs (CVOs) are small structures without a blood–brain barrier surrounding the brain ventricles that serve homeostasic functions and facilitate communication between the blood, cerebrospinal fluid and brain. Secretory CVOs release peptides and sensory CVOs regulate signal transmission. However, pathogens may enter the brain through the CVOs and trigger neuroinflammation and neurodegeneration. We investigated the feasibility of dynamic contrast-enhanced (DCE) MRI to assess the CVO permeability characteristics in vivo, and expected significant contrast uptake in these regions, due to blood–brain barrier absence. Methods Twenty healthy, middle-aged to older males underwent brain DCE MRI. Pharmacokinetic modeling was applied to contrast concentration time-courses of CVOs, and in reference to white and gray matter. We investigated whether a significant and positive transfer from blood to brain could be measured in the CVOs, and whether this differed between secretory and sensory CVOs or from normal-appearing brain matter. Results In both the secretory and sensory CVOs, the transfer constants were significantly positive, and all secretory CVOs had significantly higher transfer than each sensory CVO. The transfer constants in both the secretory and sensory CVOs were higher than in the white and gray matter. Conclusions Current measurements confirm the often-held assumption of highly permeable CVOs, of which the secretory types have the strongest blood-to-brain transfer. The current study suggests that DCE MRI could be a promising technique to further assess the function of the CVOs and how pathogens can potentially enter the brain via these structures. Trial registration: Netherlands Trial Register number: NL6358, date of registration: 2017-03-24

scholarly journals Diphenhydramine as a selective probe to study H+-antiporter function at the blood–brain barrier: Application to [11C]diphenhydramine positron emission tomography imaging

2016 ◽  
Vol 37 (6) ◽  
pp. 2185-2195 ◽  
Author(s):  
Sylvain Auvity ◽  
Hélène Chapy ◽  
Sébastien Goutal ◽  
Fabien Caillé ◽  
Benoit Hosten ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Positron Emission Tomography Imaging ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Tomography Imaging ◽  
Blood Brain ◽  
Positron Emission ◽  
The Brain

Diphenhydramine, a sedative histamine H1-receptor (H1R) antagonist, was evaluated as a probe to measure drug/H+-antiporter function at the blood–brain barrier. In situ brain perfusion experiments in mice and rats showed that diphenhydramine transport at the blood–brain barrier was saturable, following Michaelis–Menten kinetics with a Km = 2.99 mM and Vmax = 179.5 nmol s−1 g−1. In the pharmacological plasma concentration range the carrier-mediated component accounted for 77% of diphenhydramine influx while passive diffusion accounted for only 23%. [14C]Diphenhydramine blood–brain barrier transport was proton and clonidine sensitive but was influenced by neither tetraethylammonium, a MATE1 (SLC47A1), and OCT/OCTN (SLC22A1-5) modulator, nor P-gp/Bcrp (ABCB1a/1b/ABCG2) deficiency. Brain and plasma kinetics of [11C]diphenhydramine were measured by positron emission tomography imaging in rats. [11C]Diphenhydramine kinetics in different brain regions were not influenced by displacement with 1 mg kg−1 unlabeled diphenhydramine, indicating the specificity of the brain positron emission tomography signal for blood–brain barrier transport activity over binding to any central nervous system target in vivo. [11C]Diphenhydramine radiometabolites were not detected in the brain 15 min after injection, allowing for the reliable calculation of [11C]diphenhydramine brain uptake clearance (Clup = 0.99 ± 0.18 mL min−1 cm−3). Diphenhydramine is a selective and specific H+-antiporter substrate. [11C]Diphenhydramine positron emission tomography imaging offers a reliable and noninvasive method to evaluate H+-antiporter function at the blood–brain barrier.

scholarly journals Human Immunodeficiency Virus Type 1 Infection Increases the In Vivo Capacity of Peripheral Monocytes To Cross the Blood-Brain Barrier into the Brain and the In Vivo Sensitivity of the Blood-Brain Barrier to Disruption by Lipopolysaccharide

2008 ◽  
Vol 82 (15) ◽  
pp. 7591-7600 ◽  
Author(s):  
Hongwei Wang ◽  
Jinglin Sun ◽  
Harris Goldstein
Keyword(s):  
Human Immunodeficiency Virus ◽  
Blood Brain Barrier ◽  
Human Immunodeficiency Virus Type ◽  
Brain Barrier ◽  
Blood Brain ◽  
Immunodeficiency Virus ◽  
The Brain ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1), introduced into the brain by HIV-1-infected monocytes which migrate across the blood-brain barrier (BBB), infects resident macrophages and microglia and initiates a process that causes HIV-1-associated neurocognitive disorders. The mechanism by which HIV-1 infection circumvents the BBB-restricted passage of systemic leukocytes into the brain and disrupts the integrity of the BBB is not known. Circulating lipopolysaccharide (LPS), which can compromise the integrity of the BBB, is significantly increased in HIV-1-infected individuals. We hypothesized that HIV-1 infection increases monocyte capacity to migrate across the BBB, which is further facilitated by a compromise of BBB integrity mediated by the increased systemic LPS levels present in HIV-1-infected individuals. To investigate this possibility, we examined the in vivo BBB migration of monocytes derived from our novel mouse model, JR-CSF/EYFP mice, which are transgenic for both a long terminal repeat-regulated full-length infectious HIV-1 provirus and ROSA-26-regulated enhanced yellow fluorescent protein. We demonstrated that JR-CSF/EYFP mouse monocytes displayed an increased capacity to enter the brain by crossing either an intact BBB or a BBB whose integrity was partially compromised by systemic LPS. We also demonstrated that the JR-CSF mouse BBB was more susceptible to disruption by systemic LPS than the control wild-type mouse BBB. These results demonstrated that HIV-1 infection increased the ability of monocytes to enter the brain and increased the sensitivity of the BBB to disruption by systemic LPS, which is elevated in HIV-1-infected individuals. These mice represent a new in vivo system for studying the mechanism by which HIV-1-infected monocytes migrate into the brain.

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