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  • 1
    Electronic Resource
    Electronic Resource
    Blood-Brain Barrier Transport of 125I-Labeled Basic Fibroblast Growth Factor (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 63-69 
    Details
    ISSN: 1573-904X
    Keywords: adsorptive-mediated transcytosis ; basic fibroblast growth factor ; blood-brain barrier ; internal carotid artery perfusion ; isolated capillaries
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was carried out to examine the blood-brain barrier(BBB) transport of human basic fibroblast growth factor (bFGF) andinvestigate its mechanism. Methods. The BBB transport of 125I-bFGF was measured by severalin vivo methods including intravenous administration, in situ internalcarotid artery perfusion, and intracerebral microinjection. The in vitrobinding of 125I-bFGF was characterized using freshly prepared bovinebrain capillaries. Results. The distribution volume of 125I-bFGF in the postvascularsupernatant increased with the perfusion time, and exceeded the spaceoccupied by the brain microvasculature and its trichloroacetic acid(TCA) precipitability was more than 90%. 125I-bFGF avidly bound toisolated bovine brain capillaries with a Bmax of 206 ± 48 pmol/mgprotein, and a Kd of 36.5 ± 15.7 nM. This binding was significantlyinhibited by unlabeled bFGF and heparin in a concentration-dependentmanner. The cationic peptides, protamine and poly-L-lysine (each 300μM), produced over 85% inhibition of 125I-bFGF binding to braincapillaries. Furthermore, glycosaminoglycans with a sulfate residue,chondroitin sulfate B and C (each 10 μg/mL) also inhibited the bindingof 125I-bFGF. The in vivo transcytosis of 125I-bFGF from the luminalside to the brain was also inhibited by the presence of heparin (10μg/mL) and poly-L-lysine (300 μM), whereas neither hyaruronic acid (10μg/mL) nor insulin (10 μM) had any effect. In addition to these results,the brain efflux index method was used to confirm that the transcytosisof 125I-bFGF from brain to blood across the BBB was negligible. Conclusions. These results suggest that 125I-bFGF is transported acrossthe BBB, possibly by an adsorptive-mediated transcytosis mechanismthat is triggered by binding to negatively charged species on the luminalmembrane surface of the brain microvasculature, such as heparansulfate proteoglycans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007570509232
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Study on Brain Interstitial Fluid Distribution and Blood-Brain Barrier Transport of Baclofen in Rats by Microdialysis (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1838-1844 
    Details
    ISSN: 1573-904X
    Keywords: baclofen ; blood-brain barrier ; microdialysis ; organic anion transport system ; probenecid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to examine the distribution in the brain interstitial fluid (ISF) and the blood-brain barrier (BBB) transport of baclofen in rats by a microdialysis technique. Methods. Following an i.v. bolus administration and/or the constant i.v. infusion of baclofen to the microdialysis cannula-bearing anesthetized rats, the concentrations of baclofen in the hippocampal ISF, whole brain tissue, cerebrospinal fluid (CSF), and plasma were determined by high-performance liquid chromatography (HPLC). Data were kinetically analyzed to estimate the transport parameters, i.e., the influx clearance (CLin) from plasma to brain and the efflux rate constant (keff) from brain to plasma, and the steady-state volume of distribution in the brain (Vd). Results. The concentrations of baclofen in ISF, whole brain tissue, and CSF at the pseudo-steady state were almost 30-fold lower than the plasma unbound concentration, suggesting the restricted distribution of baclofen in the brain. The estimated values of CLin and keff were 0.00157 ± 0.00076 ml/min/g of brain and 0.0872 ± 0.0252 min−1, respectively. The efflux clearance (CLout) calculated by multiplying keff by Vd (0.816 ± 0.559 ml/g of brain) was 0.0712 ± 0.0529 ml/min/g of brain, and it was significantly 40-fold greater than the CLin value and fully greater than the convective flow in ISF. Furthermore, no significant concentration gradient was observed between ISF and CSF. These results suggest that the CLout value mainly reflects the efflux clearance through the BBB. Additionally, the hippocampal ISF/plasma concentration ratio of baclofen was markedly increased by both systemic administration of probenecid and its direct instillation into ISF. Conclusions. The restricted distribution of baclofen in the brain ISF may be ascribed to the efficient efflux from the brain through the BBB which is regulated possibly by a probenecid-sensitive organic anion transport system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016263032765
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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