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  1. Article: New systems for delivery of drugs to the brain in neurological disease.

    Cornford, Eain M / Cornford, Marcia E

    The Lancet. Neurology

    2003  Volume 1, Issue 5, Page(s) 306–315

    Abstract: The restricted or regulated entry of most blood-borne substances into the brain has been recognised for more than a century. The blood-brain barrier (BBB)-shielding function provided by endothelial cells is important in the treatment of neurological ... ...

    Abstract The restricted or regulated entry of most blood-borne substances into the brain has been recognised for more than a century. The blood-brain barrier (BBB)-shielding function provided by endothelial cells is important in the treatment of neurological diseases because this exclusion of foreign substances also restricts entry of many potentially therapeutic agents into the brain. The recent identification of several neuroactive proteins of potential therapeutic value has highlighted the crucial need for effective and safe transcapillary delivery methods to the brain. One promising method is delivery through brain capillaries by augmentation of pinocytotic vesicles delivery systems that use this cellular mechanism are in development. Recent investigations in animal models show that large molecules of neurotherapeutic potential can be conjugated to peptidomimetic ligands, which bind to selected peptide receptors, and are then internalised and transported in small vesicles across the cytoplasmic brain capillary barrier. These conjugates have been shown to remain functionally active and effective in animal models of neurological disease.
    MeSH term(s) Animals ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/physiology ; Brain Diseases/drug therapy ; Drug Delivery Systems/methods ; Drug Delivery Systems/trends ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Humans ; Ligands ; Liposomes/pharmacology ; Pinocytosis/drug effects ; Pinocytosis/physiology ; Recombinant Fusion Proteins/pharmacology
    Chemical Substances Ligands ; Liposomes ; Recombinant Fusion Proteins
    Language English
    Publishing date 2003-06-25
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 2081241-3
    ISSN 1474-4422
    ISSN 1474-4422
    DOI 10.1016/s1474-4422(02)00136-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5955: Show issues Location:
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  2. Article: Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy.

    Cornford, Eain M / Hyman, Shigeyo

    NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics

    2005  Volume 2, Issue 1, Page(s) 27–43

    Abstract: Immunogold electron microscopy has identified a variety of blood-brain barrier (BBB) proteins with transporter and regulatory functions. For example, isoforms of the glucose transporter, protein kinase C (PKC), and caveolin-1 are BBB specific. Isoform 1 ... ...

    Abstract Immunogold electron microscopy has identified a variety of blood-brain barrier (BBB) proteins with transporter and regulatory functions. For example, isoforms of the glucose transporter, protein kinase C (PKC), and caveolin-1 are BBB specific. Isoform 1 of the facilitative glucose transporter family (GLUT1) is expressed solely in endothelial (and pericyte) domains, and approximately 75% of the protein is membrane-localized in humans. Evidence is presented for a water cotransport function of BBB GLUT1. A shift in transporter polarity characterized by increased luminal membrane GLUT1 is seen when BBB glucose transport is upregulated; but a greater abluminal membrane density is seen in the human BBB when GLUT1 is downregulated. PKC colocalizes with GLUT1 within these endothelial domains during up- and downregulation, suggesting that a PKC-mediated mechanism regulates human BBB glucose transporter expression. Occludin and claudin-5 (like other tight-junctional proteins) exhibit a restricted distribution, and are expressed solely within interendothelial clefts of the BBB. GFAP (glial fibrillary acidic protein) is uniformly expressed throughout the foot-processes and the entire astrocyte. But the microvascular-facing membranes of the glial processes that contact the basal laminae are also polarized, and their transporters may also redistribute within the astrocyte. Monocarboxylic acid transporter and water channel (Aquaporin-4) expression are enriched at the glial foot-process, and both undergo physiological modulation. We suggest that as transcytosis and efflux mechanisms generate interest as potential neurotherapeutic targets, electron microscopic confirmation of their site-specific expression patterns will continue to support the CNS drug discovery process.
    MeSH term(s) Animals ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/physiology ; Brain Chemistry/physiology ; Capillaries/metabolism ; Carrier Proteins/metabolism ; Caveolin 1 ; Caveolins/metabolism ; Glucose Transporter Type 1 ; Humans ; Immunohistochemistry ; Microscopy, Immunoelectron ; Monocarboxylic Acid Transporters/metabolism ; Monosaccharide Transport Proteins/metabolism ; Neuroglia/metabolism ; Protein Kinase C/metabolism
    Chemical Substances CAV1 protein, human ; Carrier Proteins ; Caveolin 1 ; Caveolins ; Glucose Transporter Type 1 ; Monocarboxylic Acid Transporters ; Monosaccharide Transport Proteins ; SLC16A7 protein, human ; SLC2A1 protein, human ; Protein Kinase C (EC 2.7.11.13)
    Language English
    Publishing date 2005-02-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 2205033-4
    ISSN 1545-5351 ; 1545-5343
    ISSN (online) 1545-5351
    ISSN 1545-5343
    DOI 10.1602/neurorx.2.1.27
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6156: Show issues Location:
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  3. Article ; Online: Non-invasive gene targeting to the fetal brain after intravenous administration and transplacental transfer of plasmid DNA using PEGylated immunoliposomes.

    Cornford, Eain M / Hyman, Shigeyo / Cornford, Marcia E / Chytrova, Gabriela / Rhee, Jennifer / Suzuki, Toshimitsu / Yamagata, Tetsushi / Yamakawa, Kazuhiro / Penichet, Manuel L / Pardridge, William M

    Journal of drug targeting

    2016  Volume 24, Issue 1, Page(s) 58–67

    Abstract: Research was undertaken to establish transplacental delivery of active genes to fetal brain by a non-viral vector, antibody-specific targeted therapeutic procedure. PEGylated immunoliposomes (PILs) containing firefly luciferase DNA under the influence of ...

    Abstract Research was undertaken to establish transplacental delivery of active genes to fetal brain by a non-viral vector, antibody-specific targeted therapeutic procedure. PEGylated immunoliposomes (PILs) containing firefly luciferase DNA under the influence of the SV40 promoter injected intravenously into near-term pregnant mice produced luminometric evidence of CNS tissue luciferase activity at 48-h post-injection in all newborn pups. In utero delivery of this pGL3 DNA was shown after a single i.v. injection in maternal and neonatal brains, spleen and lesser amounts in lungs, with only negligible background levels in negative controls exposed to unencapsulated pDNA. In addition to studies of normal wild-type mice, we similarly injected pregnant Lafora Knockout (EPM2a null-mutant) and demonstrated luciferase activity days later in the maternal and newborn pup brains of both types. Delivery of PILs containing a second reporter gene (the pSV40 beta-galactosidase transgene) transplacentally by the same procedure was also successful. Histochemical and biochemical demonstration of beta-galactosidase was documented for all mutant and non-mutant neonates. Brain areas of highest Lafora body development (such as the hippocampus and pontine nuclei) showed intraneuronal beta-glucosidase activity. We conclude that receptor-mediated transport of PIL-borne gene therapeutics across both the placental barrier as well as the fetal BBB in utero is feasible.
    MeSH term(s) Administration, Intravenous ; Animals ; Brain/metabolism ; Endocytosis ; Female ; Fetus/metabolism ; Gene Targeting/methods ; Genes, Reporter ; Lafora Disease/genetics ; Liposomes/chemistry ; Liposomes/immunology ; Luciferases, Firefly/administration & dosage ; Luciferases, Firefly/genetics ; Luciferases, Firefly/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Placenta/metabolism ; Plasmids/metabolism ; Polyethylene Glycols/chemistry ; Pregnancy ; Promoter Regions, Genetic/drug effects ; Receptors, Transferrin/metabolism ; Tissue Distribution ; Transgenes/drug effects ; beta-Galactosidase/metabolism
    Chemical Substances Liposomes ; Receptors, Transferrin ; Polyethylene Glycols (30IQX730WE) ; Luciferases, Firefly (EC 1.13.12.7) ; beta-Galactosidase (EC 3.2.1.23)
    Language English
    Publishing date 2016
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1187110-6
    ISSN 1029-2330 ; 1061-186X
    ISSN (online) 1029-2330
    ISSN 1061-186X
    DOI 10.3109/1061186X.2015.1055569
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4481: Show issues Location:
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  4. Article: Immunogold detection of microvascular proteins in the compromised blood-brain barrier.

    Cornford, Eain M / Hyman, Shigeyo / Cornford, Marcia E

    Methods in molecular medicine

    2003  Volume 89, Page(s) 161–175

    MeSH term(s) Animals ; Blood Proteins/metabolism ; Blood-Brain Barrier/physiology ; Brain/blood supply ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/ultrastructure ; Epitopes/analysis ; Glial Fibrillary Acidic Protein/metabolism ; Glucose Transporter Type 1 ; Humans ; Immunohistochemistry ; Microcirculation/metabolism ; Microcirculation/ultrastructure ; Microscopy, Immunoelectron/methods ; Monosaccharide Transport Proteins/metabolism ; Particle Size ; Rats ; Staining and Labeling ; Tissue Embedding ; Tissue Fixation
    Chemical Substances Blood Proteins ; Epitopes ; Glial Fibrillary Acidic Protein ; Glucose Transporter Type 1 ; Monosaccharide Transport Proteins ; SLC2A1 protein, human
    Language English
    Publishing date 2003
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ISSN 1543-1894
    ISSN 1543-1894
    DOI 10.1385/1-59259-419-0:161
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Regional analyses of CNS microdialysate glucose and lactate in seizure patients.

    Cornford, Eain M / Shamsa, Kamran / Zeitzer, Jamie M / Enriquez, Cathleen M / Wilson, Charles L / Behnke, Eric J / Fried, Itzhak / Engel, Jerome

    Epilepsia

    2002  Volume 43, Issue 11, Page(s) 1360–1371

    Abstract: Purpose: To correlate glucose (and lactate) results obtained from microdialysate to recent studies suggesting that glucose transporter activity may be significantly altered in seizures.: Methods: We used a fluorometric technique to quantify glucose ... ...

    Abstract Purpose: To correlate glucose (and lactate) results obtained from microdialysate to recent studies suggesting that glucose transporter activity may be significantly altered in seizures.
    Methods: We used a fluorometric technique to quantify glucose and lactate levels in microdialysates collected from two to four depth electrodes implanted per patient in the temporal and frontal lobes of a series of four patients. Hour-by-hour and day-to-day changes in brain glucose and lactate levels at the same site were recorded. Additionally we compared regional variations in lactate/glucose ratios around the predicted epileptogenic region.
    Results: Lactate/glucose ratios in the range of 1-2:1 were the most commonly seen. When the lactate/glucose ratio was <1:1, we typically observed a relative increase in local glucose concentration (rather than decreased lactate), suggesting increased transport, perhaps without increased glycolysis. In some sites, lactate/glucose ratios of 3:1-15:1 were seen, suggesting that a circumscribed zone of inhibition of tricarboxylic acid cycle activity may have been locally induced. In these dialysates, collected from probes closer to the epileptogenic region, the large increase in lactate/glucose ratios was a result of both increased lactate and reduced glucose levels.
    Conclusions: We conclude that regional variations in brain extracellular glucose concentrations may be of greater magnitude than previously believed and become even more accentuated in partial seizure patients. Data from concomitant assays of microdialysate lactate and glucose may aid in understanding cerebral metabolism.
    MeSH term(s) Adult ; Brain/metabolism ; Epilepsy, Complex Partial/metabolism ; Extracellular Space/metabolism ; Female ; Fluorometry ; Glucose/metabolism ; Humans ; Lactic Acid/metabolism ; Male ; Microdialysis ; Osmolar Concentration ; Tissue Distribution
    Chemical Substances Lactic Acid (33X04XA5AT) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2002-09-04
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 216382-2
    ISSN 1528-1167 ; 0013-9580
    ISSN (online) 1528-1167
    ISSN 0013-9580
    DOI 10.1046/j.1528-1157.2002.01602.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 475: Show issues

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  6. Article: Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice.

    Ganesh, Subramaniam / Delgado-Escueta, Antonio V / Sakamoto, Toshiro / Avila, Maria Rosa / Machado-Salas, Jesus / Hoshii, Yoshinobu / Akagi, Takumi / Gomi, Hiroshi / Suzuki, Toshimitsu / Amano, Kenji / Agarwala, Kishan Lal / Hasegawa, Yuki / Bai, Dong-Sheng / Ishihara, Tokuhiro / Hashikawa, Tsutomu / Itohara, Shigeyoshi / Cornford, Eain M / Niki, Hiroaki / Yamakawa, Kazuhiro

    Human molecular genetics

    2002  Volume 11, Issue 11, Page(s) 1251–1262

    Abstract: Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous ... ...

    Abstract Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4-12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death.
    MeSH term(s) Animals ; Ataxia/physiopathology ; Behavior, Animal ; Cell Death ; Dual-Specificity Phosphatases ; Electroencephalography ; Epilepsies, Myoclonic/physiopathology ; Female ; Inclusion Bodies/metabolism ; Lafora Disease/genetics ; Lafora Disease/pathology ; Lafora Disease/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutagenesis, Site-Directed ; Neurons/metabolism ; Neurons/ultrastructure ; Protein Tyrosine Phosphatases/deficiency ; Protein Tyrosine Phosphatases/genetics ; Protein Tyrosine Phosphatases/physiology ; Ubiquitin/metabolism
    Chemical Substances Ubiquitin ; Dual-Specificity Phosphatases (EC 3.1.3.48) ; Epm2a protein, mouse (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
    Language English
    Publishing date 2002-05-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/11.11.1251
    Database MEDical Literature Analysis and Retrieval System OnLINE

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