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12 results on '"MESH : Blood-Brain Barrier"'

1. Meningococcal Type IV Pili Recruit the Polarity Complex to Cross the Brain Endothelium

Author

Xavier Nassif, Guillaume Duménil, Florence Miller, Mathieu Coureuil, Pierre-Olivier Couraud, Babette B. Weksler, Hervé Lécuyer, Christine Bernard, Ignacio A. Romero, Sandrine Bourdoulous, René-Marc Mège, Guillain Mikaty, INSERM U1002, Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Medical College of Cornell University [New York], Department of Biological Sciences, The Open University [Milton Keynes] (OU), Pathogénie des infections systémiques ( UMR_S 570 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), The Open University [Milton Keynes] ( OU ), and Coureuil, Mathieu

Subjects
MESH : Cell Line, Delta Catenin, Cell Cycle Proteins, blood brain barrier, Neisseria meningitidis, medicine.disease_cause, Cell junction, MESH : cdc42 GTP-Binding Protein, Bacterial Adhesion, MESH: Cadherins, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, MESH : Cell Cycle Proteins, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Cell polarity, MESH: Endothelial Cells, MESH : Adaptor Proteins, Signal Transducing, cdc42 GTP-Binding Protein, MESH: Antigens, CD, Protein Kinase C, 0303 health sciences, Multidisciplinary, Cell adhesion molecule, MESH : Fimbriae, Bacterial, Brain, Cell Polarity, meningitis, Catenins, Cadherins, endothelial cells, 3. Good health, Cell biology, Endothelial stem cell, Intercellular Junctions, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine.anatomical_structure, Cdc42 GTP-Binding Protein, Blood-Brain Barrier, MESH : Intercellular Junctions, MESH: Cell Adhesion Molecules, MESH : Cadherins, MESH: Endothelium, Vascular, MESH: Membrane Proteins, MESH: Cell Polarity, MESH : Cell Polarity, MESH : Bacterial Adhesion, Biology, Blood–brain barrier, MESH: Phosphoproteins, Article, MESH: Neisseria meningitidis, MESH : Cell Adhesion Molecules, Cell Line, MESH: Fimbriae, Bacterial, MESH: Brain, 03 medical and health sciences, MESH: Cell Cycle Proteins, Antigens, CD, MESH : Antigens, CD, medicine, Humans, MESH : Protein Kinase C, MESH: Bacterial Adhesion, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Catenins, Adaptor Proteins, Signal Transducing, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Humans, MESH: cdc42 GTP-Binding Protein, MESH : Endothelial Cells, MESH : Neisseria meningitidis, Cadherin, MESH : Humans, Membrane Proteins, Phosphoproteins, MESH: Protein Kinase C, MESH : Catenins, MESH: Cell Line, MESH : Brain, MESH : Endothelium, Vascular, MESH : Membrane Proteins, Fimbriae, Bacterial, Endothelium, Vascular, MESH : Phosphoproteins, Cell Adhesion Molecules, 030217 neurology & neurosurgery, MESH: Intercellular Junctions
Abstract

Breaking the Barrier Being able to deliver drugs into the brain to treat degenerative diseases such as Alzheimer's or Parkinson's requires the ability to traverse the blood-brain barrier (BBB). Understanding the formation of the very specific adherent junctions (AJ) and tight junctions present at the BBB cell junctions is a prerequisite to the design of such therapeutics. However, diminishing the expression of any one component involved in the formation of these intercellular junctions destroys them. Coureuil et al. (p. 83 , published online 11 June) exploited the specific recruitment of AJ proteins by Neisseria meningitidis to dissect this process. Adhesion of the bacteria to human brain endothelial cells recruited the polarity complex Par3/Par6/PKCζ required for the establishment of eukaryotic cell polarity and the formation of intercellular junctions. The bacterial recruitment of the polarity complex depleted junctional proteins at the cell-cell interface opening the intercellular junctions at the brainendothelial interface.

Published
2009
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2. Human Blood-Brain Barrier Disruption by Retroviral-Infected Lymphocytes: Role of Myosin Light Chain Kinase in Endothelial Tight-Junction Disorganization

Author

Marie-Christine Prévost, Christine Schmitt, Simona Ozden, Antoine Gessain, Babette B. Weksler, Pierre-Emmanuel Ceccaldi, Philippe V. Afonso, Pierre-Olivier Couraud, Ignacio A. Romero, Danielle Seilhean, Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Microscopie électronique (Plate-forme), Institut Pasteur [Paris], CHU Pitié-Salpêtrière [APHP], Weill Medical College of Cornell University [New York], Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Department of Biological Sciences, The Open University [Milton Keynes] (OU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie, Hôpital de la Salpétrière, and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, MESH : Cerebellum, [SDV]Life Sciences [q-bio], MESH : Lymphocytes, MESH : Herpesviridae Infections, MESH : Models, Immunological, MESH : Herpesvirus 8, Human, MESH : Blood-Brain Barrier, 0302 clinical medicine, Cerebellum, Interleukin-1alpha, Tropical spastic paraparesis, Immunology and Allergy, Lymphocytes, Transcellular, Cell Line, Transformed, MESH : Tumor Necrosis Factor-alpha, Human T-lymphotropic virus 1, 0303 health sciences, MESH : Neoplasm Recurrence, Local, Tight junction, MESH : Neurodegenerative Diseases, MESH : Cell Line, Transformed, Neurodegenerative Diseases, MESH : Human T-lymphotropic virus 1, Paraparesis, Tropical Spastic, 3. Good health, Cell biology, MESH : Pleural Effusion, Malignant, medicine.anatomical_structure, Spinal Cord, Blood-Brain Barrier, Paracellular transport, Infiltration (medical), medicine.medical_specialty, Myosin light-chain kinase, Endothelium, Immunology, MESH : Lymphoma, AIDS-Related, Biology, MESH : Myosin-Light-Chain Kinase, MESH : Lymphoma, Myosin light chain kinase activity, Tight Junctions, 03 medical and health sciences, medicine, Humans, MESH : Interleukin-1alpha, Myosin-Light-Chain Kinase, 030304 developmental biology, MESH : Tight Junctions, Tumor Necrosis Factor-alpha, MESH : Endothelial Cells, MESH : Humans, Models, Immunological, Endothelial Cells, Membrane Proteins, MESH : Spinal Cord, Phosphoproteins, medicine.disease, MESH : Paraparesis, Tropical Spastic, MESH : Endothelium, Vascular, MESH : Membrane Proteins, Zonula Occludens-1 Protein, Endothelium, Vascular, MESH : Phosphoproteins, 030217 neurology & neurosurgery
Abstract

The blood-brain barrier (BBB), which constitutes the interface between blood and cerebral parenchyma, has been shown to be disrupted during retroviral associated neuromyelopathies. Human T cell leukemia virus (HTLV-1)-associated myelopathy/tropical spastic paraparesis is a slowly progressive neurodegenerative disease, in which evidence of BBB breakdown has been demonstrated by the presence of lymphocytic infiltrates in the CNS and plasma protein leakage through cerebral endothelium. Using an in vitro human BBB model, we investigated the cellular and molecular mechanisms involved in endothelial changes induced by HTLV-1-infected lymphocytes. We demonstrate that coculture with infected lymphocytes induces an increase in paracellular endothelial permeability and transcellular migration, via IL-1α and TNF-α secretion. This disruption is associated with tight junction disorganization between endothelial cells, and alterations in the expression pattern of tight junction proteins such as zonula occludens 1. These changes could be prevented by inhibition of the NF-κB pathway or of myosin light chain kinase activity. Such disorganization was confirmed in histological sections of spinal cord from an HTLV-1-associated myelopathy/tropical spastic paraparesis patient. Based on this BBB model, the present data indicate that HTLV-1-infected lymphocytes can induce BBB breakdown and may be responsible for the CNS infiltration that occurs in the early steps of retroviral-associated neuromyelopathies.

Published
2007
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3. Expression of drug transporters at the blood–brain barrier using an optimized isolated rat brain microvessel strategy

Author

Salah Yousif, Françoise Roux, Xavier Declèves, Cynthia Marie-Claire, Jean-Michel Scherrmann, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique (NAVVEC - UM 81 (UMR 8206/ U705)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Marie-Claire, Cynthia, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique ( NAVVEC (UM 81) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Male, MESH : RNA, Messenger, MESH : Multidrug Resistance-Associated Proteins, MESH: Rats, Sprague-Dawley, MESH : Microcirculation, MESH : P-Glycoprotein, MESH: Membrane Transport Proteins, MESH : Blood-Brain Barrier, Rats, Sprague-Dawley, MESH: Blood-Brain Barrier, 0302 clinical medicine, MESH : Membrane Transport Proteins, MESH: Microcirculation, Gene expression, MESH: Glial Fibrillary Acidic Protein, MESH: Animals, MESH: Endothelial Cells, Microvessel, MESH: Cerebral Arteries, MESH : Organ Culture Techniques, 0303 health sciences, MESH : Gene Expression Regulation, biology, MESH : Rats, General Neuroscience, Isolated brain, MESH : Glial Fibrillary Acidic Protein, MESH: Gene Expression Regulation, Multidrug Resistance-Associated Protein 2, Blot, medicine.anatomical_structure, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Blood-Brain Barrier, cardiovascular system, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH : Carrier Proteins, Multidrug Resistance-Associated Proteins, MESH: Multidrug Resistance-Associated Proteins, Astrocyte, MESH: P-Glycoprotein, MESH: Rats, MESH : Male, MESH: Carrier Proteins, Blood–brain barrier, 03 medical and health sciences, Organ Culture Techniques, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Glial Fibrillary Acidic Protein, medicine, Animals, ATP Binding Cassette Transporter, Subfamily B, Member 1, RNA, Messenger, Molecular Biology, MESH: RNA, Messenger, 030304 developmental biology, MESH : Endothelial Cells, MESH : Cerebral Arteries, Microcirculation, MESH: Biological Markers, Endothelial Cells, Membrane Transport Proteins, Cerebral Arteries, Molecular biology, MESH : Rats, Sprague-Dawley, MESH: Organ Culture Techniques, MESH: Male, Rats, MESH : Biological Markers, Gene Expression Regulation, nervous system, Synaptophysin, biology.protein, MESH : Animals, Neurology (clinical), Neuron, Carrier Proteins, Biomarkers, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Quantitative RT-PCR (qRT-PCR) and Western blotting studies on transporters at the blood-brain barrier (BBB) of isolated brain microvessels have produced conflicting data on their cellular distribution. A major problem is identifying cells expressing the genes of interest, since isolated brain microvessels are composed of several cell types and may be contaminated with mRNA or proteins from astrocytes and neurons. We isolated rat brain microvessels and examined microscopically samples at each step of isolation to evaluate microvessel purity. The expression of specific markers of endothelial cells (Glut-1, Flk-1), pericytes (Ng2), neurons (synaptophysin, Syn) and astrocytes (Gfap) was measured by qRT-PCR in order to select the protocol giving the least astrocyte and neuron mRNAs and the most endothelial mRNAs. We also evaluated the gene expression of drug transporters (Mdr1a, Mdr1b, Mrp1-5, Bcrp and Oatp-2) at each step to optimize their location in cells at the BBB. The Mdr1a, Mrp4, Bcrp and Oatp-2 gene profiles were similar to those of endothelium markers. The profiles of Mrp2 and Mrp3 closely resembled that of Ng2. Mrp5 and Mrp1 expression was not increased in the microvessel-enriched fraction, suggesting that they are ubiquitously expressed throughout the cortex parenchyma. We also evaluated by Western blotting the expression of P-gp, Mrp2, Gfap and Syn in the cortex and in the purest obtained microvessel fraction. Our results showed that P-gp expression strongly increased in microvessels whereas Mrp2 was not detected in any of the fraction. Surprisingly, Gfap expression increased in isolated microvessels whereas Syn was not detected. Our results showed that the strategy consisting of identifying gene expression at different steps of the protocol is useful to identify cells containing mRNA at the BBB and give overall similar results with protein expression.

Published
2007
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4. Carrier-mediated processes at several rat brain interfaces determine the neuropharmacokinetics of morphine and morphine-6-β-d-glucuronide

Author

Fanchon Bourasset, Jean-Michel Scherrmann, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique (NAVVEC - UM 81 (UMR 8206/ U705)), Université Paris Diderot - Paris 7 (UPD7)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Diderot - Paris 7 (UPD7), Scherrmann, Jean-Michel, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique ( NAVVEC (UM 81) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Male, MESH : Narcotics, Microdialysis, MESH : Morphine Derivatives, MESH: Probenecid, MESH : Models, Biological, Pharmacology, Renal Agents, 030226 pharmacology & pharmacy, MESH : Spectrophotometry, Ultraviolet, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, 0302 clinical medicine, Cerebrospinal fluid, MESH: Spectrophotometry, Ultraviolet, MESH: Animals, MESH: Microdialysis, General Pharmacology, Toxicology and Pharmaceutics, MESH : Algorithms, 0303 health sciences, Morphine, Probenecid, MESH : Rats, Chemistry, Brain, General Medicine, MESH: Narcotics, Blood-Brain Barrier, MESH: Permeability, MESH: Morphine Derivatives, MESH : Renal Agents, MESH : Carrier Proteins, MESH : Probenecid, Glucuronide, Algorithms, medicine.drug, Narcotics, MESH: Rats, MESH : Male, MESH: Algorithms, MESH: Carrier Proteins, MESH : Rats, Wistar, Models, Biological, Permeability, General Biochemistry, Genetics and Molecular Biology, MESH: Brain, 03 medical and health sciences, Pharmacokinetics, In vivo, MESH : Microdialysis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Morphine Derivatives, MESH: Models, Biological, MESH : Morphine, Transporter, MESH: Rats, Wistar, MESH: Male, Rats, MESH: Morphine, MESH : Permeability, MESH : Brain, MESH: Renal Agents, Spectrophotometry, Ultraviolet, MESH : Animals, Carrier Proteins
Abstract

International audience; We investigated whether capacity-limited transport processes were involved in morphine and morphine-6-beta-D-glucuronide (M6G) neuropharmacokinetics, at the level of the blood-brain barrier (BBB), the brain extra- and intra-cellular fluids (bECF/bICF), and the bECF/cerebrospinal fluid (CSF) interfaces. We performed transcortical retrodialysis in the rat, by perfusing morphine or M6G through the microdialysis probe in the presence or absence of probenecid. We measured for each compound the in vitro and in vivo (R(D)) probe recoveries. The in vivo R(D), which takes into account the permeability of the tissue surrounding the probe, informs about the morphine and M6G distribution capabilities from bECF to adjacent fluids (bICF, CSF, plasma). We also measured plasma and CSF concentrations at three time points after having added probenecid or not. Finally, we tested several pharmacokinetic models, assuming first-order or capacity-limited processes at each brain interface, to describe experimental morphine and M6G concentrations previously obtained in rat plasma and brain fluids. We found that morphine distributes more easily outside bECF than M6G. Adding probenecid caused a 2-fold decrease and a 1.3-fold increase in morphine and M6G R(D), respectively, and 30 min after adding probenecid, plasma and CSF concentrations increased for M6G but not for morphine. The pharmacokinetic model that gave the best fit included capacity-limited processes at the BBB and bECF/bICF interface for morphine and at the BBB and bECF/CSF interface for M6G. In conclusion, morphine accumulates into brain cells thanks to a probenecid-sensitive transporter located at the bECF/bICF interface, whereas M6G is trapped in bECF thanks to transporters located at the BBB and the bECF/CSF interface.

Published
2006
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5. Correlation between in vitro cytotoxicity and in vivo lethal activity in mice of epsilon toxin mutants from Clostridium perfringens

Author

Dorca Arévalo, Jonatan, Pauillac, Serge, Díaz Hidalgo, Laura, Martín Satué, Mireia, Popoff, Michel R., Blasi Cabús, Joan, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Universitat de Barcelona ( UB ), Bactéries anaérobies et Toxines, Institut Pasteur [Paris], This work was supported by grant SAF2011-27566 (MINECO, Spanish Government) and grant 2009 SGR 152 from AGAUR (Generalitat de Catalunya), The authors thank Inmaculada Gómez de Aranda and the CCiTUB Biology Unit of the Campus de Bellvitge for their technical assistance. We are also grateful to Dr. Mark S. McClain (Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee) for his valuable comments and discussions., Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Universitat de Barcelona (UB), Institut Pasteur [Paris] (IP), and Universitat de Barcelona

Subjects
Male, Clostridium perfringens, Toxicology, Mouse models, MESH : Green Fluorescent Proteins, Madin Darby Canine Kidney Cells, MESH: Dogs, Mice, MESH: Structure-Activity Relationship, Membrane proteins, Toxin Binding, Toxins, MESH: Animals, Kidney Tubules, Distal, lcsh:Science, MESH: Clostridium perfringens, Brain, Veterinary Diseases, Neurology, Medical Microbiology, MESH: Epithelial Cells, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Neurotoxicology, MESH : Clostridium perfringens, Cell Physiology, Multiple Sclerosis, MESH: Gene Expression, Recombinant Fusion Proteins, Primary Cell Culture, Immunology, Toxic Agents, Microbiology, Structure-Activity Relationship, MESH: Green Fluorescent Proteins, MESH: Kidney Tubules, Distal, MESH: Recombinant Fusion Proteins, MESH : Primary Cell Culture, Microbial Pathogens, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, lcsh:R, Biology and Life Sciences, Cell binding, Survival Analysis, MESH : Kidney Tubules, Distal, Cell membranes, Confocal microscopy, MESH : Gene Expression, MESH : Brain, Mutation, Clostridium Infections, MESH: Enterotoxemia, Veterinary Science, lcsh:Q, Membranes cel·lulars, Veterinary Microbiology, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, Veterinary Toxicology, Gene Expression, lcsh:Medicine, Epithelial cells, MESH: Blood-Brain Barrier, MESH : Blood-Brain Barrier, MESH : Dogs, Molecular Cell Biology, MESH : Structure-Activity Relationship, Medicine and Health Sciences, Cèl·lules epitelials, MESH : Epithelial Cells, Blood-Brain Barrier, MESH: Survival Analysis, MESH : Mutation, Research Article, MESH: Mutation, MESH : Recombinant Fusion Proteins, MESH: Biological Transport, MESH: Clostridium Infections, MESH : Male, Bacterial Toxins, Green Fluorescent Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Autoimmune Diseases, MESH: Primary Cell Culture, MESH: Brain, Dogs, MESH : Mice, Animals, MESH: Mice, MESH : Enterotoxemia, MESH : Madin Darby Canine Kidney Cells, MESH: Madin Darby Canine Kidney Cells, Biological Transport, Kidneys, Cell Biology, Demyelinating Disorders, MESH: Male, MESH : Clostridium Infections, MESH : Biological Transport, MESH: Bacterial Toxins, Membrane Trafficking, Toxines, MESH : Bacterial Toxins, Clinical Immunology, MESH : Animals, MESH : Survival Analysis, Enterotoxemia
Abstract

International audience; Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein with a lethal effect on livestock, producing severe enterotoxemia characterized by general edema and neurological alterations. Site-specific mutations of the toxin are valuable tools to study the cellular and molecular mechanism of the toxin activity. In particular, mutants with paired cysteine substitutions that affect the membrane insertion domain behaved as dominant-negative inhibitors of toxin activity in MDCK cells. We produced similar mutants, together with a well-known non-toxic mutant (Etx-H106P), as green fluorescent protein (GFP) fusion proteins to perform in vivo studies in an acutely intoxicated mouse model. The mutant (GFP-Etx-I51C/A114C) had a lethal effect with generalized edema, and accumulated in the brain parenchyma due to its ability to cross the blood-brain barrier (BBB). In the renal system, this mutant had a cytotoxic effect on distal tubule epithelial cells. The other mutants studied (GFP-Etx-V56C/F118C and GFP-Etx-H106P) did not have a lethal effect or cross the BBB, and failed to induce a cytotoxic effect on renal epithelial cells. These data suggest a direct correlation between the lethal effect of the toxin, with its cytotoxic effect on the kidney distal tubule cells, and the ability to cross the BBB.

Published
2014
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6. Plasminogen in cerebrospinal fluid originates from circulating blood

Author

Cyrille Orset, Sara Martinez de Lizarrondo, Alexandre Mansour, Eduardo Anglés-Cano, G. Pepe, Anna Mezzapesa, Sabrina Matà, Denis Vivien, Guglielmina Chimienti, Loïc Doeuvre, Laurent Plawinski, Dupuis, Christine, Department of Biosciences, Biotechnologies, and Biopharmaceutics, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Università degli Studi di Firenze = University of Florence (UniFI)-Careggi Hospital, Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), We acknowledge financial support from ADISU Puglia, Consorzio Interuniversità per le Biotecnologie, Italy, and Società Italiana di Biochimica e Biologia Molecolare for the mobility to AM., Università degli studi di Bari Aldo Moro (UNIBA), Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Inserm, Università degli studi di Bari, Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de la Recherche Scientifique ( CNRS ), Università degli Studi di Firenze [Firenze], Innovations thérapeutiques en hémostase ( IThEM - U1140 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Careggi Hospital, Chimie et Biologie des Membranes et des Nanoobjets ( CBMN ), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux ( ENITAB ) -Centre National de la Recherche Scientifique ( CNRS ), and Careggi Hospital-University of Florence

Subjects
Male, MESH: Inflammation, Pathology, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Lipopolysaccharide, MESH : Microscopy, Fluorescence, MESH: Microscopy, Fluorescence, MESH : Blotting, Western, Systemic inflammation, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, chemistry.chemical_compound, Cerebrospinal fluid, Blood-cerebrospinal fluid barrier, MESH: Plasminogen, MESH: Animals, MESH : Rats, General Neuroscience, 3. Good health, medicine.anatomical_structure, Neurology, MESH : Plasminogen, Blood-Brain Barrier, Immunohistochemistry, Choroid plexus, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, medicine.medical_specialty, LPS, MESH: Rats, MESH : Male, Central nervous system, Blotting, Western, Immunology, Inflammation, MESH : Rats, Wistar, Blood–cerebrospinal fluid barrier, Cellular and Molecular Neuroscience, medicine, MESH : Choroid plexus, Animals, Humans, MESH: Blotting, Western, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Inflammation, MESH: Humans, business.industry, Multiple sclerosis, Research, MESH : Humans, [ SDV.BIO ] Life Sciences [q-bio]/Biotechnology, Plasminogen, MESH: Choroid plexus, MESH: Rats, Wistar, medicine.disease, MESH: Male, Rats, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, chemistry, Microscopy, Fluorescence, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Animals, business
Abstract

Background Plasminogen activation is a ubiquitous source of fibrinolytic and proteolytic activity. Besides its role in prevention of thrombosis, plasminogen is involved in inflammatory reactions in the central nervous system. Plasminogen has been detected in the cerebrospinal fluid (CSF) of patients with inflammatory diseases; however, its origin remains controversial, as the blood–CSF barrier may restrict its diffusion from blood. Methods We investigated the origin of plasminogen in CSF using Alexa Fluor 488–labelled rat plasminogen injected into rats with systemic inflammation and blood–CSF barrier dysfunction provoked by lipopolysaccharide (LPS). Near-infrared fluorescence imaging and immunohistochemistry fluorescence microscopy were used to identify plasminogen in brain structures, its concentration and functionality were determined by Western blotting and a chromogenic substrate assay, respectively. In parallel, plasminogen was investigated in CSF from patients with Guillain-Barré syndrome (n = 15), multiple sclerosis (n = 19) and noninflammatory neurological diseases (n = 8). Results Endogenous rat plasminogen was detected in higher amounts in the CSF and urine of LPS-treated animals as compared to controls. In LPS-primed rats, circulating Alexa Fluor 488–labelled rat plasminogen was abundantly localized in the choroid plexus, CSF and urine. Plasminogen in human CSF was higher in Guillain-Barré syndrome (median = 1.28 ng/μl (interquartile range (IQR) = 0.66 to 1.59)) as compared to multiple sclerosis (median = 0.3 ng/μl (IQR = 0.16 to 0.61)) and to noninflammatory neurological diseases (median = 0.27 ng/μl (IQR = 0.18 to 0.35)). Conclusions Our findings demonstrate that plasminogen is transported from circulating blood into the CSF of rats via the choroid plexus during inflammation. Our data suggest that a similar mechanism may explain the high CSF concentrations of plasminogen detected in patients with inflammation-derived CSF barrier impairment. Electronic supplementary material The online version of this article (doi:10.1186/s12974-014-0154-y) contains supplementary material, which is available to authorized users.

Published
2014
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7. Cell-penetrating anti-GFAP VHH and corresponding fluorescent fusion protein VHH-GFP spontaneously cross the blood-brain barrier and specifically recognize astrocytes: application to brain imaging

Author

Jean-Pierre Bourgeois, Anne-Marie Le Sourd, Fabienne Glacial, Pierre Lafaye, Susanna Celli, Pierre-Olivier Couraud, Babette B. Weksler, Ignacio A. Romero, Tengfei Li, Salah Mecheri, François Rougeon, Production de Protéines Recombinantes et d'Anticorps (Plate-Forme), Institut Pasteur [Paris] (IP), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des Interactions Hôte-Parasite, Division of Hematology and Oncology, Weill Medical College of Cornell University [New York], Department of Life, Health and Chemical Sciences, The Open University [Milton Keynes] (OU), Génétique et Biochimie du Développement, Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Gènes, Synapses et Cognition, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), and The Open University [Milton Keynes] ( OU )

Subjects
MESH : Cell Line, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Plasmodium berghei, MESH : Immunohistochemistry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Fluorescent Antibody Technique, Biochemistry, law.invention, Green fluorescent protein, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, Mice, 0302 clinical medicine, law, MESH: Glial Fibrillary Acidic Protein, MESH : Female, MESH: Animals, MESH: Fluorescent Antibody Technique, [ SDV.IB.IMA ] Life Sciences [q-bio]/Bioengineering/Imaging, 0303 health sciences, biology, Glial fibrillary acidic protein, intrabodies, MESH: Enzyme-Linked Immunosorbent Assay, Brain, MESH : Enzyme-Linked Immunosorbent Assay, MESH : Glial Fibrillary Acidic Protein, Immunohistochemistry, nanobodies, MESH : Mutagenesis, Site-Directed, 3. Good health, MESH: Mutagenesis, Site-Directed, medicine.anatomical_structure, Blood-Brain Barrier, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Single-Domain Antibodies, Recombinant DNA, Female, Antibody, Biotechnology, MESH: Cell Line, Tumor, MESH : Recombinant Fusion Proteins, Recombinant Fusion Proteins, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, fluobodies, Enzyme-Linked Immunosorbent Assay, MESH : Mice, Inbred C57BL, Astrocytoma, Blood–brain barrier, MESH: Single-Domain Antibodies, camelids, Cell Line, 03 medical and health sciences, MESH: Brain, Antigen, MESH: Mice, Inbred C57BL, Cell Line, Tumor, MESH : Mice, Glial Fibrillary Acidic Protein, Genetics, medicine, MESH: Recombinant Fusion Proteins, MESH: Plasmodium berghei, Animals, Humans, Molecular Biology, MESH: Mice, MESH : Plasmodium berghei, 030304 developmental biology, MESH: Humans, MESH : Cell Line, Tumor, MESH : Humans, MESH : Astrocytes, MESH : Astrocytoma, MESH: Immunohistochemistry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Single-Domain Antibodies, central nervous system, Fusion protein, Molecular biology, MESH: Cell Line, MESH: Astrocytes, Mice, Inbred C57BL, MESH : Fluorescent Antibody Technique, MESH: Astrocytoma, MESH : Brain, Astrocytes, biology.protein, Mutagenesis, Site-Directed, Paratope, MESH : Animals, BBB, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Antibodies normally do not cross the blood-brain barrier (BBB) and cannot bind an intracellular cerebral antigen. We demonstrate here for the first time that a new class of antibodies can cross the BBB without treatment. Camelids produce native homodimeric heavy-chain antibodies, the paratope being composed of a single-variable domain called VHH. Here, we used recombinant VHH directed against human glial fibrillary acidic protein (GFAP), a specific marker of astrocytes. Only basic VHHs (e.g., pI=9.4) were able to cross the BBB in vitro (7.8 vs. 0% for VHH with pI=7.7). By intracarotid and intravenous injections into live mice, we showed that these basic VHHs are able to cross the BBB in vivo, diffuse into the brain tissue, penetrate into astrocytes, and specifically label GFAP. To analyze their ability to be used as a specific transporter, we then expressed a recombinant fusion protein VHH-green fluorescent protein (GFP). These "fluobodies" specifically labeled GFAP on murine brain sections, and a basic variant (pI=9.3) of the fusion protein VHH-GFP was able to cross the BBB and to label astrocytes in vivo. The potential of VHHs as diagnostic or therapeutic agents in the central nervous system now deserves attention.

Published
2012
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8. Chemical optimization of new ligands of the low-density lipoprotein receptor as potential vectors for central nervous system targeting

Author

Jean Martinez, Michel Khrestchatisky, Vincent Lisowski, Marion David, Franck Debarbieux, Patrick Vlieghe, Karima Abouzid, Aude Faucon, Nadine Payrot, Geneviève Rougon, Guillaume Jacquot, Nicolas Floquet, Jean-Daniel Malcor, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Centre National de la Recherche Scientifique ( CNRS ) -Université de la Méditerranée - Aix-Marseille 2, Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Phage display, MESH: Transcytosis, MESH : Receptors, LDL, Peptide, Ligands, 01 natural sciences, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, MESH: Spinal Cord, Mice, MESH: Structure-Activity Relationship, MESH : Peptides, Cyclic, MESH : Structure-Activity Relationship, Drug Discovery, MESH: Ligands, MESH : Fluorescent Dyes, MESH: Animals, Receptor, chemistry.chemical_classification, MESH : Ligands, 0303 health sciences, MESH : Transcytosis, Chemistry, MESH: Fluorescent Dyes, Cell biology, Spinal Cord, Transcytosis, Biochemistry, Blood-Brain Barrier, Drug delivery, MESH: Oligopeptides, Molecular Medicine, Oligopeptides, MESH: Models, Molecular, MESH : Oligopeptides, MESH : Models, Molecular, MESH : Mice, Inbred C57BL, Biopanning, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, Peptides, Cyclic, Structure-Activity Relationship, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Mice, Animals, Humans, MESH: Mice, MESH: Peptides, Cyclic, Fluorescent Dyes, 030304 developmental biology, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Magnetic Resonance Spectroscopy, MESH : Humans, MESH : Spinal Cord, 0104 chemical sciences, Mice, Inbred C57BL, Receptors, LDL, Docking (molecular), MESH: Receptors, LDL, LDL receptor, MESH : Magnetic Resonance Spectroscopy, MESH : Animals
Abstract

International audience; Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.

Published
2012
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9. The impact of erythropoietin on short-term changes in phosphorylation of brain protein kinases in a rat model of traumatic brain injury

Author

Hana Lahrech, Pierre Bouzat, Emmanuel L. Barbier, Myriam Bernaudin, Régine Farion, Gilles Francony, Christoph Segebarth, Jean François Payen, Chantal Rémy, Valentine Bouet, Marie Cécile Fevre, Nouara Mahious, Samuel Valable, Edwige Petit, INSERM U836, équipe 5, Neuro-imagerie fonctionnelle et métabolique, Centre-Imagerie, Neurosciences, et Application aux Pathologies (CI-NAPS - UMR 6232), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service d'anesthésie-réanimation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Groupe Mémoire et Plasticité comportementale (GMPc), Normandie Université (NU)-Normandie Université (NU), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM) Institut pour la Recherche sur la Moelle Epiniere et l'Encephale (IRME) Association Francaise contre les Myopathies (AFM) Centre National de la Recherche Scientifique (CNRS) Ligue contre le Cancer Ministere de l'Education, de la Recherche et de la Technologie, France. Epoetin alfa (Eprex) INSERM U836 Universite Joseph Fourier, Grenoble, France, Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), INSERM U836, équipe 5, Neuroimagerie fonctionnelle et perfusion cérébrale, Pôle Anesthésie Réanimation, CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anesthésie-réanimation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Neuroimagerie Fonctionnelle et Metabolique, Inserm U836, équipe 7, Nanomédecine et cerveau, Neuro-imagerie fonctionnelle et métabolique ( ANTE-INSERM U836, équipe 5 ), Grenoble Institut des Neurosciences ( GIN ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Hôpital Michallon-Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Hôpital Michallon, Groupe Mémoire et Plasticité comportementale ( GMPc ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre-Imagerie, Neurosciences, et Application aux Pathologies ( CI-NAPS - UMR 6232 ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ) -Service d'anesthésie-réanimation, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Hôpital Michallon-Hôpital Michallon, and Dojat, Michel

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, MAPK/ERK pathway, MESH: Brain Edema, Brain Edema, MESH : Blotting, Western, Pharmacology, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, MESH: Recombinant Proteins, MESH : Phosphorylation, 0302 clinical medicine, Edema, inhibitors, Medicine, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Animals, Phosphorylation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, biology, MESH : Brain Injuries, Kinase, MESH : Rats, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Recombinant Proteins, 3. Good health, MAPK activation after brain trauma, Neurology, Blood-Brain Barrier, Mitogen-activated protein kinase, MESH : Erythropoietin, Recombinant, [ SCCO.NEUR ] Cognitive science/Neuroscience, Original Article, brain trauma, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Brain Edema, medicine.symptom, Cardiology and Cardiovascular Medicine, EPO (erythropoietin), MESH: Rats, Traumatic brain injury, MESH : Recombinant Proteins, MESH : Male, Blotting, Western, MESH : Protein Kinases, MESH : Rats, Wistar, Cerebral edema, 03 medical and health sciences, Animals, Humans, MESH: Blotting, Western, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rats, Wistar, Erythropoietin, Protein kinase B, MESH: Protein Kinases, 030304 developmental biology, MESH: Humans, MAPK (mitogen-activated protein kinase), MESH: Phosphorylation, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, MESH : Humans, MESH: Erythropoietin, Recombinant, MESH: Rats, Wistar, medicine.disease, MESH : Disease Models, Animal, MESH: Male, Rats, Disease Models, Animal, cerebral edema, Brain Injuries, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Immunology, MESH: Brain Injuries, biology.protein, Neurology (clinical), MESH : Animals, MESH: Disease Models, Animal, business, Protein Kinases, 030217 neurology & neurosurgery
Abstract

International audience; We found that recombinant human erythropoietin (rhEPO) reduced significantly the development of brain edema in a rat model of diffuse traumatic brain injury (TBI) (impact-acceleration model). In this study, we investigated the molecular and intracellular changes potentially involved in these immediate effects. Brain tissue nitric oxide (NO) synthesis, phosphorylation level of two protein kinases (extracellular-regulated kinase (ERK)-1/-2 and Akt), and brain water content were measured 1 (H1) and 2 h (H2) after insult. Posttraumatic administration of rhEPO (5,000 IU/kg body weight, intravenously, 30 mins after injury) reduced TBI-induced upregulation of ERK phosphorylation, although it increased Akt phosphorylation at H1. These early molecular changes were associated with a reduction in brain NO synthesis at H1 and with an attenuation of brain edema at H2. Intraventricular administration of the ERK-1/-2 inhibitor, U0126, or the Akt inhibitor, LY294002, before injury showed that ERK was required for brain edema formation, and that rhEPO-induced reduction of edema could involve the ERK pathway. These results were obtained in the absence of any evidence of blood-brain barrier damage on contrast-enhanced magnetic resonance images. The findings of our study indicate that the anti edematous effect of rhEPO could be mediated through an early inhibition of ERK phosphorylation after diffuse TBI.

Published
2010
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10. UDP-glucuronosyltransferases (UGTs) in neuro-olfactory tissues: expression, regulation, and function

Author

Yves Artur, Jean-Marie Heydel, Nicolas Thiebaud, Arièle Legendre, Elzbieta J. Holsztynska, Anne-Marie Le Bon, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), and Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)

Subjects
Olfactory system, MESH : RNA, Messenger, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, MESH: Glucuronosyltransferase, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, chemistry.chemical_compound, 0302 clinical medicine, MESH: Smell, Pharmacology (medical), MESH: Animals, MESH: Uridine Diphosphate, MESH: Nerve Tissue Proteins, Glucuronosyltransferase, General Pharmacology, Toxicology and Pharmaceutics, MESH : Olfactory Bulb, MESH : Nerve Tissue Proteins, 0303 health sciences, MESH: Gene Expression Regulation, Enzymologic, Olfactory Pathways, Olfactory Bulb, MESH : Odors, Cell biology, Smell, medicine.anatomical_structure, Blood-Brain Barrier, MESH: Olfactory Bulb, medicine.medical_specialty, Central nervous system, Nerve Tissue Proteins, In situ hybridization, Olfaction, Biology, digestive system, Gene Expression Regulation, Enzymologic, Olfactory Receptor Neurons, Uridine Diphosphate, MESH : Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Internal medicine, medicine, Animals, RNA, Messenger, MESH : Uridine Diphosphate, 030304 developmental biology, MESH: RNA, Messenger, MESH: Odors, MESH : Olfactory Pathways, MESH : Glucuronosyltransferase, MESH: Olfactory Receptor Neurons, Olfactory bulb, Uridine diphosphate, Endocrinology, chemistry, Odorants, MESH : Smell, MESH : Olfactory Receptor Neurons, MESH : Animals, Olfactory epithelium, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Function (biology), MESH: Olfactory Pathways
Abstract

International audience; This work aims to review uridine diphosphate (UDP)-glucuronosyltransferase (UGT) expression and activities along different neuronal structures involved in the common physiological process of olfaction: olfactory epithelium, olfactory bulb, and olfactory cortex. For the first time, using high-throughput in situ hybridization data generated by the Allen Brain Atlas (ABA), we present quantitative analysis of spatial distribution of UGT genes in the mouse brain. The olfactory area is a central nervous system site with the highest expression of UGTs, including UGT isoforms not previously identified in the brain. Since there is evidence of the transfer of xenobiotics to the brain through the nasal pathway, circumventing the blood-brain barrier, olfactory UGTs doubtlessly share the common function of detoxification, but they are also involved in the metabolism and turnover of exogenous or endogenous compounds critical for physiological olfactory processing in these tissues. The function of olfactory UGTs will be discussed with a special focus on their participation in the perireceptor events involved in the modulation of olfactory perception.

Published
2010
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11. Synthesis, radiosynthesis and biological evaluation of 1,4-dihydroquinoline derivatives as new carriers for specific brain delivery

Author

Lénaïg Foucout, Ahmed Abbas, Jean Costentin, Fabienne Gourand, Pierre Bohn, Vincent Levacher, Francis Marsais, Louisa Barré, Martine Dhilly, Georges Dupas, Asymétrie, hétérocycles, hétérochimie et bio-organique (AHHBO), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Centre-Imagerie, Neurosciences, et Application aux Pathologies (CI-NAPS - UMR 6232), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropsycho-pharmacologie expérimentale, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychologie cognitive et neuroanatomie fonctionnelles de la mémoire humaine, Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Asymétrie, hétérocycles, hétérochimie et bio-organique ( AHHBO ), Centre National de la Recherche Scientifique ( CNRS ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes ( LITIS ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Centre-Imagerie, Neurosciences, et Application aux Pathologies ( CI-NAPS - UMR 6232 ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ), Normandie Université ( NU ) -Normandie Université ( NU ) -École pratique des hautes études ( EPHE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), and Breton, Céline

Subjects
Nervous system, Male, MESH: Oxidation-Reduction, MESH : NAD, MESH: Radiochemistry, MESH: gamma-Aminobutyric Acid, Pharmacology, 01 natural sciences, Biochemistry, [ SDV.IB.MN ] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, MESH : Blood-Brain Barrier, MESH : Carbon Radioisotopes, MESH: Blood-Brain Barrier, chemistry.chemical_compound, Mice, MESH: Animals, Carbon Radioisotopes, MESH: Carbon Radioisotopes, gamma-Aminobutyric Acid, Drug Carriers, Radiochemistry, Chemistry, MESH : Rats, Quinoline, Radiosynthesis, Brain, MESH: NAD, MESH : gamma-Aminobutyric Acid, MESH: Motor Activity, MESH: Drug Carriers, medicine.anatomical_structure, Blood-Brain Barrier, Quinolines, GABAergic, MESH : Hydrophobicity, Hydrophobic and Hydrophilic Interactions, Oxidation-Reduction, MESH: Quinolines, MESH : Drug Carriers, MESH: Rats, MESH : Quinolines, MESH : Male, MESH: Biological Transport, Central nervous system, MESH : Radiochemistry, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Motor Activity, 010402 general chemistry, Redox, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, MESH: Brain, In vivo, MESH : Mice, medicine, Animals, Physical and Theoretical Chemistry, MESH: Mice, MESH : Oxidation-Reduction, MESH: Hydrophobicity, 010405 organic chemistry, Organic Chemistry, Biological Transport, NAD, In vitro, MESH: Male, 0104 chemical sciences, Rats, MESH : Biological Transport, MESH : Brain, MESH : Animals, MESH : Motor Activity
Abstract

International audience; In spite of numerous reports dealing with the use of 1,4-dihydropyridines as carriers to deliver biological active compounds to the brain, this chemical delivery system (CDS) suffers from poor stability of the 1,4-dihydropyridine derivatives towards oxidation and hydration reactions seriously limiting further investigations in vivo. In an attempt to overcome these limitations, we report herein the first biological evaluation of more stable annellated NADH models in the quinoline series as relevant neuroactive drug-carrier candidates. The radiolabeled 1,4-dihydroquinoline [(11)C] was prepared to be subsequently peripherally injected in rats. The injected animals were sacrificed and brains were collected. The radioactivity measured in rat brain indicated a rapid penetration of the carrier [(11)C] into the CNS. HPLC analysis of brain homogenates showed that oxidation of [(11)C] into the corresponding quinolinium salt [(11)C] was completed in less than 5 min. An in vivo evaluation in mice is also reported to illustrate the potential of such 1,4-dihydroquinoline derivatives to transport a neuroactive drug in the CNS. For this purpose, gamma-aminobutyric acid (GABA), well known to poorly cross the brain blood barrier (BBB) was connected to this 1,4-dihydroquinoline-type carrier. After i.p. injection of 1,4-dihydroquinoline-GABA derivative in mice, a significant alteration of locomotor activity (LMA) was observed presumably resulting from an enhancement of central GABAergic activity. These encouraging results give strong evidence for the capacity of carrier-GABA derivative to cross the BBB and exert a pharmacological effect on the CNS. This study paves the way for further progress in designing new redox chemical delivery systems.

Published
2009
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12. Alteration of blood-brain barrier integrity by retroviral infection

Author

Sophie Lambert, Pierre-Emmanuel Ceccaldi, Pierre-Olivier Couraud, Philippe V. Afonso, S. Mason, Marie-Christine Cumont, Luis Cartier, Simona Ozden, Claudine Pique, Danielle Seilhean, Ignacio A. Romero, Michel Huerre, Payam Rezaie, Antoine Gessain, Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Histotechnologie et Pathologie, Institut Pasteur [Paris] (IP), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Facultad de Medicina, School of Life, Health and Chemical Sciences [Milton Keynes], Faculty of Science, Technology, Engineering and Mathematics [Milton Keynes], The Open University [Milton Keynes] (OU)-The Open University [Milton Keynes] (OU), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from the Association pour la Recherche sur la Scle´rose en Plaques (ARSEP) and the Institut Pasteur (Programme Transversal de Recherche number 190) and the Pasteur-Fiocruz grants. PVA is a grant recipient from the Ministe`re de la Recherche (France)., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Gau, Mireille, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Universidad de Santiago de Chile [Santiago] ( USACH ), Department of Life Sciences, The Open University [Milton Keynes] ( OU ), Institut Cochin ( UMR_S567 / UMR 8104 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
MESH : Cell Line, MESH: Paraparesis, Tropical Spastic, Lymphocyte, MESH : Retroviridae Infections, MESH: Tight Junctions, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, MESH: Spinal Cord, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, immune system diseases, hemic and lymphatic diseases, Neuropilin 1, MESH: Endothelial Cells, Biology (General), MESH : Autopsy, 0303 health sciences, Human T-lymphotropic virus 1, virus diseases, MESH : Human T-lymphotropic virus 1, Paraparesis, Tropical Spastic, 3. Good health, Cell biology, Endothelial stem cell, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Spinal Cord, Blood-Brain Barrier, MESH: Retroviridae Infections, Receptors, Virus, Autopsy, Research Article, Cell type, QH301-705.5, Immunology, Central nervous system, Biology, Blood–brain barrier, Microbiology, Cell Line, Tight Junctions, 03 medical and health sciences, Virology, Infectious Diseases/Viral Infections, Genetics, medicine, Humans, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, MESH : Tight Junctions, MESH: Human T-lymphotropic virus 1, MESH: Humans, Infectious Diseases/Infectious Diseases of the Nervous System, MESH : Endothelial Cells, MESH : Humans, Endothelial Cells, MESH : Spinal Cord, RC581-607, Virology/Host Invasion and Cell Entry, MESH: Receptors, Virus, MESH: Cell Line, MESH : Paraparesis, Tropical Spastic, Cell culture, biology.protein, Parasitology, GLUT1, MESH : Receptors, Virus, Immunologic diseases. Allergy, MESH: Autopsy, 030217 neurology & neurosurgery, Retroviridae Infections
Abstract

The blood–brain barrier (BBB), which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans), both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies., Author Summary The blood–brain barrier (BBB) forms the interface between the blood and the central nervous system (CNS). BBB disruption is considered to be a key event in the pathogenesis of retroviral-associated neurological diseases. The present paper deals with the susceptibility of the endothelial cells (i.e., one of the main cellular components of BBB) to retroviral infection, and with the impact of infection in BBB function. This study focuses on the Human T-Lymphotropic Virus (HTLV-1), which infects 20 million people worldwide, and is the etiological agent of a neurodegenerative disease called HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). We first demonstrated that the cerebral endothelial cells express the receptors for the retrovirus in vitro, and on spinal cord autopsy sections from non-infected and HAM/TSP patients. We found on these latter that vascular-like structures were infected and confirmed in vitro that the endothelial cells could be productively infected by HTLV-1. We demonstrated that such an infection impairs BBB properties in vitro, as well as tight junctions, that are cell adhesion structures. This study is the first to demonstrate the impact of HTLV-1 infection on human BBB integrity; such a susceptibility has to be considered in the design of future therapeutics strategies.

Published
2008
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