• Journal of Radiopharmaceuticals and Molecular Probes
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• v.8 no.1
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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.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.3
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• pp.239-252
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• 2024

Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 ㎍/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 ㎍/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways.

• BMB Reports
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• v.49 no.5
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• pp.255-262
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• 2016

The disease known as cerebral cavernous malformations mostly occurs in the central nervous system, and their typical histological presentations are multiple lumen formation and vascular leakage at the brain capillary level, resulting in disruption of the blood-brain barrier. These abnormalities result in severe neurological symptoms such as seizures, focal neurological deficits and hemorrhagic strokes. CCM research has identified 'loss of function' mutations of three ccm genes responsible for the disease and also complex regulation of multiple signaling pathways including the WNT/β-catenin pathway, TGF-β and Notch signaling by the ccm genes. Although CCM research is a relatively new and small scientific field, as CCM research has the potential to regulate systemic blood vessel permeability and angiogenesis including that of the blood-brain barrier, this field is growing rapidly. In this review, I will provide a brief overview of CCM pathogenesis and function of ccm genes based on recent progress in CCM research.

• Proceedings of the PSK Conference
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• 2001.04a
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• pp.161.2-161.2
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• 2001

• Journal of Korean Neurosurgical Society
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• v.47 no.3
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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.

• Reproductive and Developmental Biology
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• v.34 no.3
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• pp.153-159
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• 2010

The 34 potently pig pheromonal odorants (1-32, 5755 & 7113) through structure-based virtual screening and ligand-based virtual screening method were selected and their ADMET and pharmacokinetics characters were evaluated and discussed quantitatively. The pheromonal odorants were projected on the following pre-calculated models, Caco-2 cell permeability, blood-brain barrier permeation, hERG inhibition and volume-distribution. From the results of in silico study, it is found that an optimal compound (31) either penetrating or have a little ($P_{caco2}$=-8.143) for Caco-2 cell permeability, moderate penetrating ability ($P_{BBB}$=0.082) for blood-brain barrier permeation, the low QT prolongation ($P_{hERG}$=1.137) for the hERG $K^+$ channel inhibition, and low distribution into tissues ($P_{VD}$=-5.468) for volume-distribution. Therefore, it is predicted that the compound (31) a topical application may be preferable from these based foundings.

• Korean Journal of Radiology
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• v.22 no.7
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• pp.1152-1162
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• 2021

Objective: This study aimed to determine whether there are regional differences in the blood-brain barrier (BBB) permeability of cognitively normal elderly participants and to identify factors influencing BBB permeability with a clinically feasible, 10-minute dynamic contrast-enhanced (DCE) MRI protocol. Materials and Methods: This IRB-approved prospective study recruited 35 cognitively normal adults (26 women; mean age, 64.5 ± 5.6 years) who underwent DCE T1-weighted imaging. Permeability maps (K_trans) were coregistered with masks to calculate the mean regional values. The paired t test and Friedman test were used to compare Ktrans between different regions. The relationships between K_trans and the factors of age, sex, education, cognition score, vascular risk burden, vascular factors on imaging, and medial temporal lobar atrophy were assessed using Pearson correlation and the Spearman rank test. Results: The mean permeability rates of the right and left hippocampi, as assessed with automatic segmentation, were 0.529 ± 0.472 and 0.585 ± 0.515 (K_trans, x 10^-3 min^-1), respectively. Concerning the deep gray matter, the K_trans of the thalamus was significantly greater than those of the putamen and hippocampus (p = 0.007, p = 0.041). Regarding the white matter, the K_trans value of the occipital white matter was significantly greater than those of the frontal, cingulate, and temporal white matter (p < 0.0001, p = 0.0007, p = 0.0002). The variations in K_trans across brain regions were not related to age, cognitive score, vascular risk burden, vascular risk factors on imaging, or medial temporal lobar atrophy in the study group. Conclusion: Our study demonstrated regional differences in BBB permeability (K_trans) in cognitively normal elderly adults using a clinically acceptable 10-minutes DCE imaging protocol. The regional differences suggest that the integrity of the BBB varies across the brains of cognitively normal elderly adults. We recommend considering regional differences in K_trans values when evaluating BBB permeability in patients with neurodegenerative diseases.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.4
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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.

• Korean Journal of Radiology
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• v.22 no.1
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• pp.118-130
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• 2021

Objective: This study aimed to investigate the blood-brain barrier (BBB) disruption in mild traumatic brain injury (mTBI) patients with post-concussion syndrome (PCS) using dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging and automatic whole brain segmentation. Materials and Methods: Forty-two consecutive mTBI patients with PCS who had undergone post-traumatic MR imaging, including DCE MR imaging, between October 2016 and April 2018, and 29 controls with DCE MR imaging were included in this retrospective study. After performing three-dimensional T1-based brain segmentation with FreeSurfer software (Laboratory for Computational Neuroimaging), the mean K^trans and v_p from DCE MR imaging (derived using the Patlak model and extended Tofts and Kermode model) were analyzed in the bilateral cerebral/cerebellar cortex, bilateral cerebral/cerebellar white matter (WM), and brainstem. K^trans values of the mTBI patients and controls were calculated using both models to identify the model that better reflected the increased permeability owing to mTBI (tendency toward higher K^trans values in mTBI patients than in controls). The Mann-Whitney U test and Spearman rank correlation test were performed to compare the mean K^trans and v_p between the two groups and correlate K^trans and v_p with neuropsychological tests for mTBI patients. Results: Increased permeability owing to mTBI was observed in the Patlak model but not in the extended Tofts and Kermode model. In the Patlak model, the mean K^trans in the bilateral cerebral cortex was significantly higher in mTBI patients than in controls (p = 0.042). The mean v_p values in the bilateral cerebellar WM and brainstem were significantly lower in mTBI patients than in controls (p = 0.009 and p = 0.011, respectively). The mean K^trans of the bilateral cerebral cortex was significantly higher in patients with atypical performance in the auditory continuous performance test (commission errors) than in average or good performers (p = 0.041). Conclusion: BBB disruption, as reflected by the increased K^trans and decreased v_p values from the Patlak model, was observed throughout the bilateral cerebral cortex, bilateral cerebellar WM, and brainstem in mTBI patients with PCS.

• Biomolecules & Therapeutics
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• v.8 no.2
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• pp.194-198
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• 2000

Taurine, 2-aminoethanesulfonic acid is widely distributed in animal tissues and has a variety of bio-logical activities. A recent worldwide study demonstrated beneficial effects of taurine on aging and age-associated disorders. In general, taurine levels in the brain decease when an animal is subjected to pathologic conditions such as ischemia-anoxia and seizure. But the taurine levles tend to increase in the brain in hypertensive state. In the present study, the blood-brain barrier (BBB) transport of [$^3$H]taurine was compared between spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley rats (SD) using intravenous injection technique in vivo. We also obtained pharmacokinetic parameters of plasma volume maker, [$^{14}$ C] sucrose and [$^3$H]taurine after inject to rats simulatenously. BBB permeability surface area product (PS) value of [$^3$H]taurine in SHR (16$\pm$2.9$\times$10$^{-3}$ ml/min/g) was significantly higher than that in SD (7.4$\pm$0.8$\times$10$^{-3}$ ml/min/g). There is also significant difference for brain uptake of [$^3$H]taurine between SHR (0.195$\pm$0.031%ID/g) and SD (0.058$\pm$0.003% ID/g). This is due to difference of area under the plasma concentration-time curve (AUC) and that of total clearance (Class) between SHR and SD. No significant difference was indicated from other organ uptakes such as lung, heart, liver SHR and SD. But also kidney uptake was much higher in SHR. In conclusion, [$^3$H]taurine in plasma was slowly eliminated in SHR than in SD and uptake of [$^3$H]taurine in SHR is much higher than that of SD. This results suggest increased taurine level in the brain in hypertension state have an any effect on the brain uptake of taurine.