scholarly journals Importance of Monocarboxylate Transporter 8 for the Blood-Brain Barrier-Dependent Availability of 3,5,3′-Triiodo-l-Thyronine

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2491-2496 ◽  
Author(s):  
Ainhoa Ceballos ◽  
Monica M. Belinchon ◽  
Eduardo Sanchez-Mendoza ◽  
Carmen Grijota-Martinez ◽  
Alexandra M. Dumitrescu ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Blood Brain Barrier ◽  
Neurodevelopmental Disorder ◽  
Genetically Engineered ◽  
Brain Barrier ◽  
Monocarboxylate Transporter ◽  
Target Cells ◽  
Relative Role ◽  
Restricted Access ◽  
Blood Brain

Mutations of the gene expressing plasma membrane transporter for thyroid hormones MCT8 (SLC16A2) in humans lead to altered thyroid hormone levels and a severe neurodevelopmental disorder. Genetically engineered defect of the Mct8 gene in mice leads to similar thyroid hormone abnormalities but no obvious impairment of brain development or function. In this work we studied the relative role of the blood-brain barrier and the neuronal plasma cell membrane in the restricted access of T3 to the target neurons. To this end we compared the effects of low doses of T4 and T3 on cerebellar structure and gene expression in wild-type (Wt) and Mct8 null male mice [Mct8-/y, knockout (KO)] made hypothyroid during the neonatal period. We found that compared with Wt animals, T4 was considerably more potent than T3 in the Mct8KO mice, indicating a restricted access of T3, but not T4, to neurons after systemic administration in vivo. In contrast, T3 action in cultured cerebellar neurons was similar in Wt cells as in Mct8KO cells. The results suggest that the main restriction for T3 entry into the neural target cells of the mouse deficient in Mct8 is at the blood-brain barrier.

scholarly journals Parallel Regulation of Thyroid Hormone Transporters OATP1c1 and MCT8 During and After Endotoxemia at the Blood-Brain Barrier of Male Rodents

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1552-1564 ◽  
Author(s):  
Gábor Wittmann ◽  
Judit Szabon ◽  
Petra Mohácsik ◽  
Shira S. Nouriel ◽  
Balázs Gereben ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Blood Brain Barrier ◽  
Organic Anion ◽  
Brain Barrier ◽  
Monocarboxylate Transporter ◽  
Mrna Levels ◽  
Brain Vessels ◽  
Altered Expression ◽  
Protein Levels ◽  
Blood Brain

Abstract There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1), and monocarboxylate transporter 8 (MCT8). MRNA levels were studied by in situ hybridization and qPCR as well as protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9 hours after LPS injection, specifically in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48 hours after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24 hours whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation.

scholarly journals Expression of the Thyroid Hormone Transporters Monocarboxylate Transporter-8 (SLC16A2) and Organic Ion Transporter-14 (SLCO1C1) at the Blood-Brain Barrier

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6251-6261 ◽  
Author(s):  
Lori M. Roberts ◽  
Kathleen Woodford ◽  
Mei Zhou ◽  
Deborah S. Black ◽  
Jill E. Haggerty ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Monocarboxylate Transporter ◽  
Hormone Deficiency ◽  
Apical Surface ◽  
Cerebral Microvessels ◽  
Mild Phenotype ◽  
Ion Transporter ◽  
Blood Brain

Thyroid hormones require transport across cell membranes to carry out their biological functions. The importance of transport for thyroid hormone signaling was highlighted by the discovery that inactivating mutations in the human monocarboxylate transporter-8 (MCT8) (SLC16A2) cause severe psychomotor retardation due to thyroid hormone deficiency in the central nervous system. It has been reported that Mct8 expression in the mouse brain is restricted to neurons, leading to the model that organic ion transporter polypeptide-14 (OATP14, also known as OATP1C1/SLCO1C1) is the primary thyroid hormone transporter at the blood-brain barrier, whereas MCT8 mediates thyroid hormone uptake into neurons. In contrast to these reports, we report here that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human, mouse, and rat. In addition, OATP14 mRNA and protein are strongly enriched in mouse and rat cerebral microvessels but not in human microvessels. In rat, Mct8 and Oatp14 proteins localize to both the luminal and abluminal microvessel membranes. In human and rodent choroid plexus epithelial cells, MCT8 is concentrated on the epithelial cell apical surface and OATP14 localizes primarily to the basal-lateral surface. Mct8 and Oatp14 expression was also observed in mouse and rat tanycytes, which are thought to form a barrier between hypothalamic blood vessels and brain. These results raise the possibility that reduced thyroid hormone transport across the blood-brain barrier contributes to the neurological deficits observed in affected patients with MCT8 mutations. The high microvessel expression of OATP14 in rodent compared with human brain may contribute to the relatively mild phenotype observed in Mct8-null mice, in contrast to humans lacking functional MCT8.

scholarly journals Dendrimeric Poly(Epsilon-Lysine) Delivery Systems for the Enhanced Permeability of Flurbiprofen across the Blood-Brain Barrier in Alzheimer’s Disease

2018 ◽  
Vol 19 (10) ◽  
pp. 3224 ◽  
Author(s):  
Shafq Al-azzawi ◽  
Dhafir Masheta ◽  
Anna Guildford ◽  
Gary Phillips ◽  
Matteo Santin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Solid Phase ◽  
Synthesis Method ◽  
Delivery Systems ◽  
Brain Barrier ◽  
Target Cells ◽  
Target Tissue ◽  
Blood Brain

Alzheimer’s disease (AD) is a progressive brain disorder and age-related disease characterised by abnormal accumulation of β-amyloid (Aβ). The development of drugs to combat AD is hampered by the lack of therapeutically-active molecules able to cross the blood-brain barrier (BBB). It is agreed that specifically-designed carriers, such as dendrimers, could support the drug penetration across the BBB. The aim of this study was to design biocompatible and biodegradable dendrimeric delivery systems able to carry Flurbiprofen (FP), as drug for AD treatment, across the BBB and liberate it at the target tissue. These dendrons were synthesised using solid-phase peptide synthesis method and characterised by mass spectrometry and fourier-transform infrared spectroscopy (FTIR). The results revealed successful synthesis of dendrons having FP been integrated during the synthesis at their branching ends. Cytotoxicity assays demonstrated the biocompatibility of the delivery systems, whereas HPLC analysis showed high percentages of permeability across an in vitro BBB model for FP-integrated dendrons. Results also revealed the efficiency of drug conjugates on the γ-secretase enzyme in target cells with evidence of eventual drug release by hydrolysis of the carrier. This study demonstrates that the coupling of FP to dendrimeric delivery systems can successfully be achieved during the synthesis of the poly(epsilon-lysine) macromolecules to improve the transport of the active drug across the BBB.

Pritumumab binding to glioma cells induces ADCC and inhibits tumor growth.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14004-e14004
Author(s):  
Santosh Kesari ◽  
Ivan Babic ◽  
Rajesh Mukthavaram ◽  
Pengfei Jiang ◽  
Natsuko Nomura ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Growth ◽  
Blood Brain Barrier ◽  
Intact Cell ◽  
Glioma Cells ◽  
Brain Barrier ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Blood Brain

e14004 Background: Pritumumab is a natural human IgG1 kappa antibody originally isolated from a regional draining lymph node of a patient with cervical carcinoma. This antibody binds ectodomain vimentin on the surface of tumor cells and has demonstrated some benefit to glioblastoma patients in limited clinical trials. We wanted to determine if pritumumab inhibits glioma growth in vivo and if binding to glioma cells induces cell-mediated immunity. Methods: Pritumumab was used in flow cytometry experiments with several glioma cell lines and patient-derived neurosphere lines. Antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay was used with glioma target cells. Xenograft studies were performed in mice with and without intact B- and NK- cells. Results: We performed flow cytometry using pritumumab antibody and demonstrate binding of pritumumab to the surface of glioma cells and patient-derived glioma initiating cells. We observed significant induction of ADCC by pritumumab binding to glioma cells. Xenograft studies demonstrated pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Intact cell-mediated immunity was necessary for pritumumab’s anti-tumor effect. Analysis of a blood brain barrier model showed significant binding of pritumumab in brain tumor areas and minimal distribution in normal brain tissues suggesting the antibody can cross the blood brain barrier. Conclusions: Our data demonstratepritumumab binds glioma cells in vitro and can induce ADCC. In addition, pritumumab can limit the growth of xenograft glioma tumors in vivo only in the presence of intact cell-mediated immunity. Together these data suggest pritumumab is suitable for development as an anti-tumor therapeutic.

scholarly journals Endothelin-1 as a Mediator of Endothelial Cell–Pericyte Interactions in Bovine Brain Capillaries

1997 ◽  
Vol 17 (4) ◽  
pp. 464-469 ◽  
Author(s):  
Marie-Pierre Dehouck ◽  
Paul Vigne ◽  
Gérard Torpier ◽  
Jean Philippe Breittmayer ◽  
Roméo Cecchelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Cortex ◽  
Bovine Brain ◽  
Brain Barrier ◽  
Target Cells ◽  
Brain Capillaries ◽  
Endothelin 1 ◽  
Blood Brain

Endothelial cells and pericytes are closely associated in brain capillaries. Together with astrocytic foot processes, they form the blood–brain barrier. Capillaries were isolated from bovine brain cortex. Pure populations of endothelial cells and pericytes were isolated and cultured in vitro. Polarized monolayers of endothelial cells preferentially secreted immunoreactive endothelin-1 (Et-1) at their abluminal (brain-facing) membrane. They did not express receptors for Et-1. Pericytes expressed BQ-123-sensitive ETA receptors for endothelins as evidenced by 125I-Et-1 binding experiments. These receptors were coupled to phospholipase C as demonstrated by intracellular calcium measurements using indo-1-loaded cells. Addition of Et-1 to pericytes induced marked changes in the cell morphology that were associated with a reorganization of F-actin and intermediate filaments. It is concluded that Et-1 is a paracrine mediator at the bovine blood–brain barrier and that capillary pericytes are target cells for endothelium-derived Et-1.

Context-Specific Function of the Engineered Peptide Domain of PHP.B

2021 ◽  
Author(s):  
R. Alexander Martino ◽  
Edwin C. Fluck ◽  
Jacqueline Murphy ◽  
Qiang Wang ◽  
Henry Hoff ◽  
...  
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Receptor Binding ◽  
Cell Types ◽  
Structural Features ◽  
Protein Domain ◽  
Brain Barrier ◽  
Target Cells ◽  
Blood Brain ◽  
The Impact

One approach to improve the utility of adeno-associated virus (AAV)-based gene therapy is to engineer the AAV capsid to 1) overcome poor transport through tissue barriers and 2) redirect the broadly tropic AAV to disease-relevant cell types. Peptide- or protein-domain insertions into AAV surface loops can achieve both engineering goals by introducing a new interaction surface on the AAV capsid. However, we understand little about the impact of insertions on capsid structure and the extent to which engineered inserts depend on a specific capsid context to function. Here, we examine insert–capsid interactions for the engineered variant AAV9-PHP.B. The 7-amino-acid peptide insert in AAV9-PHP.B facilitates transport across the murine blood–brain barrier via binding to the receptor Ly6a. When transferred to AAV1, the engineered peptide does not bind Ly6a. Comparative structural analysis of AAV1-PHP.B and AAV9-PHP.B revealed that the inserted 7-amino-acid loop is highly flexible and has remarkably little impact on the surrounding capsid conformation. Our work demonstrates that Ly6a binding requires interactions with both the PHP.B peptide and specific residues from the AAV9 HVR VIII region. An AAV1-based vector that incorporates a larger region of AAV9-PHP.B—including the 7-amino-acid loop and adjacent HVR VIII amino acids—can bind to Ly6a and localize to brain tissue. However, unlike AAV9-PHP.B, this AAV1-based vector does not penetrate the blood–brain barrier. Here we discuss the implications for AAV capsid engineering and the transfer of engineered activities between serotypes. Importance Targeting AAV vectors to specific cellular receptors is a promising strategy for enhancing expression in target cells or tissues while reducing off-target transgene expression. The AAV9-PHP.B/Ly6a interaction provides a model system with a robust biological readout that can be interrogated to better understand the biology of AAV vectors’ interactions with target receptors. In this work, we analyzed the sequence and structural features required to successfully transfer the Ly6a receptor-binding epitope from AAV9-PHP.B to another capsid of clinical interest: AAV1. We found that AAV1- and AAV9-based vectors targeted to the same receptor exhibited different brain-transduction profiles. Our work suggests that, in addition to attachment-receptor binding, the capsid context in which this binding occurs is important for a vector’s performance.

scholarly journals Antibody Neutralization of HIV-1 Crossing the Blood-Brain Barrier

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Valérie Lorin ◽  
Anne Danckaert ◽  
Françoise Porrot ◽  
Olivier Schwartz ◽  
Philippe V. Afonso ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Brain Damage ◽  
Blood Brain Barrier ◽  
Neutralizing Antibodies ◽  
Brain Barrier ◽  
Brain Cells ◽  
Target Cells ◽  
Blood Brain ◽  
The Brain ◽  
Hiv 1

ABSTRACT HIV-1 can cross the blood-brain barrier (BBB) to penetrate the brain and infect target cells, causing neurocognitive disorders as a result of neuroinflammation and brain damage. Here, we examined whether antibodies targeting the HIV-1 envelope glycoproteins interfere with the transcytosis of virions across the human BBB endothelium. We found that although the viral envelope spike gp160 is required for optimal endothelial cell endocytosis, no anti-gp160 antibodies blocked the BBB transcytosis of HIV-1 in vitro. Instead, both free viruses and those in complex with antibodies transited across endothelial cells in the BBB model, as observed by confocal microscopy. HIV-1 infectious capacity was considerably altered by the transcytosis process but still detectable, even in the presence of nonneutralizing antibodies. Only virions bound by neutralizing antibodies lacked posttranscytosis infectivity. Overall, our data support the role of neutralizing antibodies in protecting susceptible brain cells from HIV-1 infection despite their inability to inhibit viral BBB endocytic transport. IMPORTANCE HIV-1 can cross the blood-brain barrier (BBB) to penetrate the brain and infect target cells, causing neurocognitive disorders as a result of neuroinflammation and brain damage. The HIV-1 envelope spike gp160 is partially required for viral transcytosis across the BBB endothelium. But do antibodies developing in infected individuals and targeting the HIV-1 gp160 glycoproteins block HIV-1 transcytosis through the BBB? We addressed this issue and discovered that anti-gp160 antibodies do not block HIV-1 transport; instead, free viruses and those in complex with antibodies can transit across BBB endothelial cells. Importantly, we found that only neutralizing antibodies could inhibit posttranscytosis viral infectivity, highlighting their ability to protect susceptible brain cells from HIV-1 infection.

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