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  • 1
    Digitale Medien
    Digitale Medien
    Kinetic Analysis of Leucine-Enkephalin Cellular Uptake at the Luminal Side of the Blood-Brain Barrier of an In Situ Perfused Guinea-Pig Brain (1989)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 53 (1989), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: The uptake of enkephalin-(5-L-leucine) (Leu-en-kephalin) at the luminal side of the blood-brain barrier was measured by means of an in situ vascular brain perfusion technique in the anaesthetized guinea pig. This method allows measurements of cerebrovascular peptide uptake over periods of up to 20 min, and excludes the solute under study from the general circulation and systemic metabolic influences. A capillary unidirectional transfer constant, Kin, for [tyrosyl-3,5-3H]Leu-enkephalin was estimated graphically from the multiple-time brain uptake data in the presence of different concentrations of unlabelled peptide, and dose-dependent self-inhibition was demonstrated. Analysis of unidirectional influx of blood-borne Leu-en kephalin into the brain revealed Michaelis-Menten saturation kinetics in the parietal cortex, caudate nucleus, and hippocampus, with Vmax between 0.14 and 0.16 nmol min−1 g−1 and Km ranging from 34 to 41 μM, for the saturable component, whereas the estimated diffusion constant, Kd, was not significantly different from zero. Entry of [3H]Leu-enkephalin was not inhibited in the presence of either a 5 mM concentration of unlabelled L-tyrosine, tyro-sylglycine, and tyrosylglycylglycine, or aminopeptidase inhibitor, bestatin (0.5 mM), suggesting that the saturable mechanism of the tracer at the luminal side of the blood-brain barrier does not involve uptake of the peptide's N-terminal amino acid and/or its tyrosine-containing fragments. The specific δ-opioid antagonist, allyl2-Tyr-AIB-Phe-OH, and μ-opioid receptor agonist, Tyr-D-Ala-Gly-Me-Phe-NH(CH2)20H, at concentrations in the perfusate above the Km value for the saturable transport of Leu-enkephalin, did not affect significantly uptake of [3H]Leu-enkephalin. The present study provides, for the first time, a characterization of the kinetic parameters of the unidirectional uptake of a peptide from the luminal side of the blood-brain barrier
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1111/j.1471-4159.1989.tb08522.x
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  • 2
    Digitale Medien
    Digitale Medien
    Cerebrovascular Accumulation and Increased Blood-Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 70 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and blood-brain barrier (BBB) permeability to 125I-amyloid β(1-40) synthetic peptide (sAβ1-40) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sAβ1-40, te1/2, was prolonged by 0.6 h, the systemic clearance, ClSS, was reduced from 1.8 to 1.1 ml/min/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sAβ1-40 was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sAβ1-40 by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, and 2.1-fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sAβ1-40 remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sAβ1-40, and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sAβ1-40, and reduced brain metabolism to enhance the development of CAA.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.70010210.x
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  • 3
    Digitale Medien
    Digitale Medien
    Isoform-Specific Effects of Apolipoproteins E2, E3, and E4 on Cerebral Capillary Sequestration and Blood-Brain Barrier Transport of Circulating Alzheimer's Amyloid β (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 69 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: Cerebral capillary sequestration and blood-brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sAβ1–40, a peptide homologous to the major form of soluble Alzheimer's amyloid β, were studied in perfused guinea pig brain. Cerebrovascular uptake of three apoE isoforms was low, their blood-to-brain transport undetectable, but uptake by the choroid plexus significant. Binding of all three isoforms to sAβ1–40 in vitro was similar with a KD between 11.8 and 12.9 nM. Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sAβ1–40-apoE2 and sAβ1–40-apoE3, but significant for sAβ1–40-apoE4. After 10 min, 85% of sAβ1–40-apoE4 taken up at the BBB remained as intact complex, whereas free sAβ1–40 was 51% degraded. Circulating apoE isoforms have contrasting effects on cerebral capillary uptake of and BBB permeability of sAβ. ApoE2 and apoE3 completely prevent cerebral capillary sequestration and blood-to-brain transport of sAβ1–40. Conversely, apoE4, by entering brain microvessels and parenchyma as a stable complex with sAβ, reduces peptide degradation and may predispose to cerebrovascular and possibly enhance parenchymal amyloid formation under pathological conditions.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69051995.x
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  • 4
    Digitale Medien
    Digitale Medien
    Transport of Dopamine at the Blood-Brain Barrier of the Guinea Pig: Inhibition by Psychotropic Drugs and Nicotine (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 290-295 
    Details
    ISSN: 1573-904X
    Schlagwort(e): dopamine ; transport ; blood-brain barrier ; guinea pigs ; nicotine ; psychotropic drugs
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. Transport of dopamine (DA) across the blood-brain barrier (BBB) was examined in guinea pigs. Methods. In situ brain perfusion (1–10 min), capillary depletion, and high pressure liquid chrbmatography (HPLC) were used. Results. There was a saturable DA influx into the brain with a KM of 389 ± 55 nM, and a VMAXof 1.95 ± 0.25 pmol/min/g of brain. The diffusion constant, KD, was not significantly different from zero. About 0.5% of DA remained tightly bound to cerebral microvessels isolated from the perfused brain. DA influx into the brain was not altered by the monoamine oxidase-B (MAO-B) inhibitor pargyline (50 µM). HPLC analysis of perfused brain confirmed transport of intact DA, and no detectable increases in DA metabolites were observed. At perfusate concentrations of 500 nM, several dopaminergic receptor antagonists inhibited [3H]-DA (21 nM) influx; the percent inhibitions for the mixed D1 and D2 antagonists haloperidol and chlorpromazine, the D1, antagonist SCH-23390, and the D2 antagonist spiperone were 90%, 68%, 77%, and 50%, respectively. Brain perfusion with nicotine (500 nM) inhibited DA uptake by 86%. This nicotine effect was not altered by mecamylamine, but was partially prevented by the nicotinic receptor antagonist hexamethonium. Conclusions. a) A significant cerebrovascular permeability to intact DA is mediated by a MAO-B independent specific transport system at the BBB, b) this system could be inhibited by D1, and D2 DA receptor antagonists, and c) DA blood-to-brain transport was inhibited by nicotine.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1016007601794
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  • 5
    Digitale Medien
    Digitale Medien
    Intravenous Infusion of RMP-7 Increases Ocular Uptake of Ganciclovir (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 80-85 
    Details
    ISSN: 1573-904X
    Schlagwort(e): blood-ocular barriers ; bradykinin ; drug delivery ; retina ; guinea pig
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. The ability of intravenous (i.v.) infusions of the bradykinin agonist, RMP-7, to permeabilize the blood-ocular barriers (BOB) to the antiviral agent ganciclovir was investigated in guinea-pigs. Methods. Different i.v. dosing regimens included pre-treatment with RMP-7 (0.2 μg/kg/min for 5 min) followed by either [3H]-ganciclovir (1 μCi/0.2 ml/min) alone, and/or co-infusion with RMP-7 and [3H]-ganciclovir. At specific times the animals were sacrificed, their eyes removed, and the retina and lens epithelium dissected and analyzed for the amount of radioactivity. Results. Using the ratio of tissue vs. integrated plasma radioactivity concentration, a two-fold increase in ganciclovir steady-state levels were observed in the retina as well as lens epithelium following RMP-7 pretreatment. Peak uptake effects were achieved with a 4.5 min ganciclovir infusion. Neither longer infusions of ganciclovir alone, nor co-infusions of RMP-7 and ganciclovir further enhanced the uptake effects. Kinetic analysis indicated that RMP-7 increased the rate of ganciclovir entry (K IN) in studied ocular tissues, while the efflux of drug (K OUT) was not affected by this treatment. Finally, ganciclovir retina:plasma ratios elevated by RMP-7 pre-treatment, remained higher than control ratios within 60 min following cessation of 4.5 min ganciclovir infusion. Conclusions. These data offer further evidence that BOB and in particular the blood-retinal barrier can be permeabilized via bradykinin receptor stimulation. As the i.v. infusions of RMP-7 enhanced the retinal uptake of ganciclovir, it is suggested that a combination of RMP-7 and ganciclovir may provide a novel approach for treating cytomegalo-virus retinis.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1012011618785
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  • 6
    Digitale Medien
    Digitale Medien
    Cereport™ (RMP-7) Increases the Permeability of Human Brain Microvascular Endothelial Cell Monolayers1 (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1360-1365 
    Details
    ISSN: 1573-904X
    Schlagwort(e): Cereport ; bradykinin B2 receptor ; human ; brain endothelium ; permeability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Purpose. To study Cereport (RMP-7, bradykinin B2 agonist) effects on human brain microvascular endothelial cell (HBMEC) monolayer permeability. Methods. HBMEC grown on transwell membranes were exposed to Cereport. The monolayer permeability was determined with [I4C]-inulin (MW. 5,200) and [3H]-dextran (MW. 70,000). Results. Cereport increased the HBMEC permeability to [l4C]-inulin, but not to [3H]-dextran. The effect was transient, maximal at 15 min (i.e., 79.3% increase), and polarized to the basolateral membrane. An inverted U, dose-response curve was observed with active concentrations of Cereport from 0.01 to 0.5 nmol/L, the plateau maximal effect between 0.5 and 10 nmol/L, and loss of activity at the highest concentration, i.e., 20 nmol/L. Cyclic AMP-specific phosphodiesterase 3 (PDE3) inhibitor rolipram (10 μmol/L) abolished Cereport effects, while cGMP-specific PDE5 inhibitor, zaniprast (50 μmol/L) enhanced by 31 % (p 〈 0.05) the effect of 0.1 nmol/L Cereport. Unlabeled Cereport displaced [12 5I]-bradykinin and/or [125I]-Cereport from the basolateral side. There was no specific Cereport binding to the apical side. Conclusions. Cereport exerts specific time, dose and size dependent actions on HMBEC monolayer that are restricted to the basolateral membrane. Its effects can be further modulated through changes in cAMP and cGMP second messenger systems.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1018938722768
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