• 대한방사성의약품학회지
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• 제8권1호
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• pp.17-23
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• 2022

Boron neutron capture therapy is a precision treatment technology that selectively destroys only tumor cells by irradiating thermal neutrons after accumulating boron drugs in tumor cells. Brain tumor is difficult to diagnose and treat due to the low permeability and targeting of drugs caused by the blood-brain-barrier. Crossing the BBB is essential for drug delivery to the brain. In this study, we designed and synthesized a novel compound incorporating benzothiazole to develop a boron drug with high BBB permeability and selectivity for brain tumor cells. In addition, their potential as a BNCT drugs was evaluated.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.199.2-200
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• 2003

Choline is an important membrane phospholipid constituent and a neurotransmitter precursor that is minimally synthesized in brain. The long-term maintenance of brain choline concentration is dependent on choline transport from plasma, which occurs via saturable transport system at the blood-brain barrier. In the present study, we examined to elucidate the characteristics of transport of cationic amines, especially choline which is one of cationic amines, to BBS using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) in vitro. (omitted)

• Journal of Pharmaceutical Investigation
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• 제30권2호
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• pp.99-105
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• 2000

This study compared the permeability of $[^3H]taurine,\;[^3H]phenylalanine,\;and\;[^3H]oxytocin$ through the blood-brain barrier (BBB) in mice and rats with common carotid artery perfusion (CCAP) method that modified internal carotid artery perfusion (ICAP) method. External carotid artery (ECA) was cannulated with coagulating pterygopalatine artery (PPA) in ICAP method, while CCA was cannulated without coagulating PPA in CCAP method. Also, for evaluation of BBB permeability of drugs in mice and rats, we used intravenous injection technique. The results of CCAP method in mice at a perfusion flow-rate of 2 ml/min, the brian volume of distribution $(V_D)$ of $[^{14}C]sucrose,\;[^3H]taurine,\;[^3H]phenylalanine,\;and\;[^3H]oxytocin$ were similar to the result of ICAP method in rats at perfusion flow rate of 4 ml/min. The area under the plasma concentration-time curve and brain uptake of $[^3H]taurine$ by intravenous injection technique, were $65.5{\pm}9.7%ID^*min/ml\;and\;0.515{\pm}0.093%ID/g$, respectively, in mice, and the corresponding values were $8.00{\pm}0.03%ID^*min/ml\;and\;0.052{\pm}0.003%ID/g$ in rats. But the BBB permeability surface-area product of $[^3H]taurine$ was similar between mice and rats. In conclusion, the CCAP method in mice was simple, fast and comparable to ICAP method in rats for drug permeability through the BBB.

• 동의생리병리학회지
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• 제23권4호
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• pp.866-871
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• 2009

Brain edema is a major importance in the pathophysiology of CNS injuries including stroke. Ischemic brain edema results from both cytotoxic edema, which is severe in astrocytes at early stage, and vasogenic edema caused by excessive blood-brain barrier (BBB) permeability. The present study was performed to determine the effect of Rhei Rhizoma on brain edema induced by middle cerebral artery occlusion (MCAO) in the rats. The neurological symptom, total infarct volume and edema index caused by MCAO were measured. The changes of Matrix Metalloproteinase-9 (MMP-9) and inducible nitric oxide synthase (iNOS) immunoreactivities were also observed. We found that Rhei Rhizoma extract improved the neurological symptom and attenuated the total infarct volume and brain edema caused by ischemic insult. Rhei Rhizoma extract also attenuated the expression of MMP-9 and iNOS. This results suggest that Rhei Rhizoma has a protective effect on the brain edema caused by ischemic insult.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.69.2-69.2
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• 2003

The purpose of this study is to examine whether the efflux system for taurine from brain to blood is present on the blood-brain barrier (BBB) using the brain efflux index (BEl) method and taurine transport system is regulated by CNS cell damage with oxidative stress agent such as diethyl maleate (DEM) or tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) in vivo. ［$^3$H]Taurine was microinjected into parietal cortex area 2 (Par2) of the rat brain, and was eliminated from the brain with efflux transport rate of 1.22 10$\^$-2//min, and the process is saturable with a $K_{m}$ of 43.5 ${\mu}$M. (omitted)

• Biomolecules & Therapeutics
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• 제10권1호
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• pp.37-42
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• 2002

Brain drug targeting through the blood-brain barrier (BBB) in vivo is possible with peptidornirnetic monoclonal antibodies that undergo receptor-mediated transcytosis through the BBB. Monoclonal antibody to the rat transferrin receptor, such as the OX26 was studied in rats as a transport vector through BBB on the transferrin receptor. But, OX26 is not an effective brain delivery vector in mouse. In the present studies, rat monoclonal antibody, 8D3 to the mouse transferrin receptor were evaluated for brain drug targeting vector intransgenic mouse model. Pharrnacokinetic parameters in plasma and organ uptakes were determined at varioustimes after i.v. bolus injection of [$^{}125}I$] 8D3 in Balb/c mice. Brain uptake of [$^{}125}I$] 8D3 was also studied with an internal carotid artery perfusioncapillary depletion method. After i.v. injection of [$^{}125}I$] 8D3, plasma concentrations declined biexponentially with elimination half lift of approximately 2.2 hours. Brain uptake of [$^{}125}I$] 8D3 was $0.50{\pm}0.09$ persent of injected dose per g brain after 2 hours i.v. injection. After perfusion 5 min the apparent volume of distibution of [$^{}125}I$] 8D3 in brain was $22.3 {\mu}l/g,$ which was 4.8 fold higher than the intravascular volume. These studies indicate rat monoclonal antibody to the mouse transferrin receptor, 8D3 may be used for brain drug targeting vector in mice.

• 대한본초학회지
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• 제29권1호
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• pp.19-26
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• 2014

Objectives : This study was performed in order to evaluate the effects of Salviae Miltiorrhizae Radix (SMR) water extract against the cerebral hemorrhage and the blood-brain barrier (BBB) impairment in the intracerebral hemorrhage (ICH). Method : ICH was induced by the stereotaxic intrastriatal injection of bacterial collagenase type IV in Sprague-Dawley rats. SMR was orally given three times every 20 hours during 3 days after the ICH induction. Hematoma volume, water content of brain tissue and volume of evans blue leakage were examined. Myeloperoxidase (MPO) positive neutrophils and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) were observed with immunofluorescence labeling and confocal microscope. Results : SMR significantly reduced the hematoma volume of the ICH-induced rat brain. SMR significantly reduced the water content of brain tissue of the ICH-induced rat brain. SMR reduced the percentage of the evans blue leakage around the hematoma on the caudate putamen compared to the ICH group, especially on the cerebral cortex. SMR significantly reduced the volume of the evans blue leakage level in the peri-hematoma regions of the ICH-induced rat brain. SMR significantly reduced MPO positive neutrophils in the peri-hematoma regions of the ICH-induced rat brain. SMR reduced the TNF-${\alpha}$ expression in peri-hematoma regions of the ICH-induced rat brain. TNF-${\alpha}$ immuno-labeled cells were coincided with MPO immuno-labeled neutrophils in peri-hematoma regions of the ICH-induced rat brain. Conclusion : These results suggest that SMR plays a protective role against the blood-brain barrier impairment in the ICH through suppression of inflammation in the rat brain tissues.

• Journal of Korean Neurosurgical Society
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• 제47권3호
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• pp.203-209
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• 2010

Objective : The purpose of study was to evaluate the feasibility of brain magnetic resonance (MR) images of the rat obtained using a 1.5T MR machine in several blood-brain barrier (BBB) experiments. Methods : Male Sprague-Dawley rats were used. MR images were obtained using a clinical 1.5T MR machine. A microcatheter was introduced via the femoral artery to the carotid artery. Normal saline (group 1, n = 4), clotted autologous blood (group 2, n = 4), triolein emulsion (group 3, n = 4), and oleic acid emulsion (group 4, n = 4) were infused into the carotid artery through a microcatheter. Conventional and diffusion-weighted images, the apparent coefficient map, perfusion-weighted images, and contrast-enhanced MR images were obtained. Brain tissue was obtained and triphenyltetrazolium chloride (TTC) staining was performed in group 2. Fluorescein isothiocyanate (FITC)-labeled dextran images and endothelial barrier antigen (EBA) studies were performed in group 4. Results : The MR images in group 1 were of good quality. The MR images in group 2 revealed typical findings of acute cerebral infarction. Perfusion defects were noted on the perfusion-weighted images. The MR images in group 3 showed vasogenic edema and contrast enhancement, representing vascular damage. The rats in group 4 had vasogenic edema on the MR images and leakage of dextran on the FITC-labeled dextran image, representing increased vascular permeability. The immune reaction was decreased on the EBA study. Conclusion : Clinical 1.5T MR images using a rat depicted many informative results in the present study. These results can be used in further researches of the BBB using combined clinical MR machines and immunohistochemical examinations.

• Biomolecules & Therapeutics
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• 제5권1호
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• pp.53-58
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• 1997

$[Lys^7$]dermorphin, abbreviated K7DA, which has structural features similar to a metabolically stable $\mu$-opioid peptide agonist $[D-Arg^2, Lys^4$]dermorphin analogue (DALDA), but is intrinsically more potent with respect to binding to the $\mu$-opioid peptide receptor. The present studies report on attempts to enhance brain uptake of systemically administered K7DA by conjugation to a complex of streptavidin (SA) and the OX26 murine monoclonal antibody to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the blood-brain barrier (BBB). SA-OX26 conjugate mediates BBB transport of biotinylated therapeutics. The K7DA is monobiotinylated at the $\varepsilon$-amino group of the $[Lys^7$] residue with cleavable linker using NHS-SS-biotin. The brain uptake of $^{125}I$ labeled biotinylated K7DA ($^{125}I$-bio-SSa-K7DA) was very small and rapidly metabolized after intravenous injection. The brain uptake, expressed as percent of injected dose delivered per gram of brain, of the $^{125}I$-bio-55-K7DA bound to the SA-OX26 conjugate $^{125}I$-bio-SS-K7DA/SA-OX26) was 0.14$\pm$0.01, a level that is 2-fold greater than the brain uptake of morphine. The cleavability of the disulfide linker in vivo in rat plasma and brain was assessed with gel filtration HPLC and intravenous injection of labeled opioid chimeric peptides. The disulfide linker is stable in plasma in vivo but is cleaved in rat brain in vivo. In conclusion, these studies show that delivery of these potential opioid peptides to the brain may be improved by coupling them to vector-mediated BBB drug delivery system.

• Journal of Pharmaceutical Investigation
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• 제20권4호
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• pp.223-228
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• 1990

The contribution of endogenous transport systems to the blood-brain barrier (BBB) transport of basic and acidic drugs was studied by using a carotid injection technique in rats and an isolated bovine cerebrovascular disease state were compared between the normotensive rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) which have been well established as an animal model with pathogenic similarities to humans. Basic drugs such as eperisone, thiamine and scopolamine inhibited, in a concentration dependent manner the in vivo uptake of $[{^3}H]choline$ through BBB, whereas amino acids and acidic drugs such as salicylic acid and valproic acid did not inhibit the uptake. The uptake of $[^3H]choline$ by B-CAP increased with time and showed a remarkable temperature dependency. The uptake of $[^3H]choline$ by B-CAP showed the very similar inhibitory effects as observed in the in vivo brain uptake, and was competitively inhibited by a basic drug, eperisone. The in vivo BBB uptakes of $[^3H]acetic$ acid and $[^{14}C]salicylic$ acid were dependent on pH of the injectate and the concentration of drugs. Several acidic drugs such such as salicylic acid, benzoic acid and valproic acid inhibited the in vivo uptake of $[^3H]acetic$ acid, whereas amino acid, choline and a basic drug such as eperisone did not inhibit the uptake. The uptake of acetic acid by B-CAP was competitively inhibited by salicylic acid. The permeability surface area product (PS) through BBB for $[^3H]choline$ in SHRSP was significantly lower than that in WKY. The concentration of choline in the brain dialysate in SHRSP was about half of that in WKY, while no significant difference was observed in the plasma concentration of choline between SHRSP and WKY. No significant difference was observed in the transport of monocarboxylic acids, glucose and neutral amino acid through BBB between SHRSP and WKY. From these results, it was concluded that BBB transport system of choline contributes to the transport of basic drugs through BBB, that acidic drugs can be transported via a moncarboxylic acid BBB transport system and that the specific dysfuntion of the BBB choline transport in SHRSP was ascribed to the reduction of the maximum velocity of choline concentration in the brain interstitial fluids.