• BMB Reports
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• 제55권5호
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• pp.213-219
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• 2022

The blood-brain barrier (BBB) is an interface between cerebral blood and the brain parenchyma. As a gate keeper, BBB regulates passage of nutrients and exogeneous compounds. Owing to this highly selective barrier, many drugs targeting brain diseases are not likely to pass through the BBB. Thus, a large amount of time and cost have been paid for the development of BBB targeted therapeutics. However, many drugs validated in in vitro models and animal models have failed in clinical trials primarily due to the lack of an appropriate BBB model. Human BBB has a unique cellular architecture. Different physiologies between human and animal BBB hinder the prediction of drug responses. Therefore, a more physiologically relevant alternative BBB model needs to be developed. In this review, we summarize major features of human BBB and current BBB models and describe organ-on-chip models for BBB modeling and their applications in neurological complications.

• 대한영상의학회지
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• 제81권3호
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• pp.488-500
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• 2020

최근의 연구들은 알츠하이머병의 병리가 단순히 아밀로이드와 타우단백질의 축적만이 아닌, 혈액뇌장벽(blood brain barrier; 이하 BBB) 이상과 같은 미세혈관병리와 밀접한 관련이 있음을 밝히고 있다. BBB 투과도 변화는 아밀로이드 및 타우 단백질 축적뿐 아니라 신경염증과 신경 퇴행성변화를 일으킴으로써 결국 임상 치매를 야기한다. 최근에는 알츠하이머 및 관련 질환의 BBB 이상을 보기 위한 MR 영상의 이용이 증가하고 있다. 이 종설에서는 알츠하이머병에서 BBB와 관련된 병리를 소개하고, BBB 투과도 변화에 대한 MR 영상 연구들을 소개할 것이다. 또한 BBB 투과도 측정을 위한 MR 방법론 개요와 문제점들을 제시할 것이다.

• Journal of Korean Neurosurgical Society
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• 제66권2호
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• pp.172-182
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• 2023

Objective : The blood-brain barrier (BBB) is an obstacle for molecules to pass through from blood to the brain. Focused ultrasound is a new method which temporarily opens the BBB, which makes pharmaceutical delivery or removal of neurodegenerative proteins possible. This study was demonstrated to review our BBB opening procedure with magnetic resonance guided images and find specific patterns in the BBB opening. Methods : In this study, we reviewed the procedures and results of two clinical studies on BBB opening using focused ultrasound regarding its safety and clinical efficacy. Magnetic resonance images were also reviewed to discover any specific findings. Results : Two clinical trials showed clinical benefits. All clinical trials demonstrated safe BBB opening, with no specific side effects. Magnetic resonance imaging showed temporary T1 contrast enhancement in the sonication area, verifying the BBB opening. Several low-signal intensity spots were observed in the T2 susceptibility-weighted angiography images, which were also reversible and temporary. Although these spots can be considered as microbleeding, evidence suggests these are not ordinary microbleeding but an indicator for adequate BBB opening. Conclusion : Magnetic resonance images proved safe and efficient BBB opening in humans, using focused ultrasound.

• Journal of Pharmaceutical Investigation
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• 제23권1호
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• pp.1-9
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• 1993

The endothelial cell of brain capillary called the blood-brain barrier (BBB) has carrier-mediated transport systems for nutrients and drugs. The mechanism of the BBB transport of basic and acidic drugs has been reviewed and examined for endogenous transport systems in BBB in WKY and SHRSP. Acidic drugs such as salicylic acid and basic drugs such as eperisone are taken up in a carrier mediated manner through the BBB via the monocarboxylic acid and amine transport systems. The specific dysfunction for the choline transport at the BBB in SHRSP would affect the function of the brain endothelial cell and brain parenchymal cell. The utilization of the endogenous transport systems of monocarboxylic acid and amine could be promising strategy for the effective drug delivery to the brain.

• BMB Reports
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• 제52권2호
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• pp.111-112
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• 2019

Although many studies have reported that the breakdown of the blood-brain barrier (BBB) represents one of the major pathological changes in aging, the mechanism underlying this process remains relatively unexplored. In this study, we described that acid sphingomyelinase (ASM) derived from endothelial cells plays a critical role in BBB disruption in aging. ASM levels were elevated in the brain endothelium and plasma of aged humans and mice, resulting in BBB leakage through an increase in caveolae-mediated transcytosis. Moreover, ASM caused damage to the caveolae-cytoskeleton via protein phosphatase 1-mediated ezrin/radixin/moesin dephosphorylation in primary mouse brain endothelial cells. Mice overexpressing brain endothelial cell-specific ASM exhibited acceleration of BBB impairment and neuronal dysfunction. However, genetic inhibition and endothelial specific knock-down of ASM in mice improved BBB disruption and neurocognitive impairment during aging. Results of this study revealed a novel role of ASM in the regulation of BBB integrity and neuronal function in aging, thus highlighting the potential of ASM as a new therapeutic target for anti-aging.

• 한국음향학회지
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• 제41권5호
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• pp.564-569
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• 2022

인체의 다른 장기들과 달리, 뇌는 혈뇌장벽(Blood-Brain Barrier, BBB)라는 보호 장치가 존재하여 뇌혈관내 물질들이 뇌조직으로 투과되는 것을 제한하는 역할을 한다. 이러한 BBB는 알츠하이머, 뇌종양 등 다양한 뇌질환에 직접적으로 전달이 필요한 약물의 투과까지 제한하기 때문에 치료 효능 검증 및 임상 적용이 어려운 것으로 보고되고 있다. 이러한 문제를 극복하기 위해 비침습적 특성의 집속 초음파(Focused Ultrasound, FUS)를 뇌의 국소 부위에 조사할 경우 마이크로버블의 음향공동화 현상으로 인해 BBB가 일시적으로 개방될 수 있는 기술이 개발되었으며, 해당 기술을 안전성 및 유효성 검증, 약물 전달 효율을 증대시킬 수 있는 다양한 연구가 전 세계적으로 수행되고 있다. 따라서, 본 논문에서는 알츠하이머, 뇌종양 등 뇌질환 치료를 위해 활발히 연구가 진행중인 집속초음파 기반 BBB 개방 기술에 대한 연구 동향을 분석하였다.

• Biomolecules & Therapeutics
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• 제18권1호
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• pp.65-70
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• 2010

The blood-brain barrier (BBB) transport of acetylcholinesterase (AChE) inhibitors, donepezil and tacrine suggested to be mediated by choline transport system in our previous study. Therefore, in the present study, we investigated the interaction of other AChE inhibitors, rivastigmine and galantamine with choline transporter at the BBB. The effects of rivastigmine and galantamine on the transport of choline by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB cells) were characterized by cellular uptake study using radiolabeled choline. The uptake of [$^3H$]choline was inhibited by rivastigmine and galantamine, with $IC_{50}$ values (i.e. concentration necessary for 50% inhibition) for 1.13 and 1.15 mM, respectively. Rivastigmine inhibited the uptake of [$^3H$]choline competitively with $K_i$ of 1.01 mM, but galantamine inhibited noncompetitively. In addition, the efflux of [$^3H$]choline was significantly inhibited by rivastigmine and galantamine. Our results indicated that the BBB choline transporter may be involved in a part of the influx and efflux transport of rivastigmine across the BBB. These findings should be therapeutically relevant to the treatment of Alzheimer's disease (AD) with AChE inhibitors, and, more generally, to the BBB transport of CNS-acting cationic drugs via choline transporter.

• Archives of Pharmacal Research
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• 제29권4호
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• pp.265-275
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• 2006

In the developing brain, capillaries are differentiated and matured into the blood-brain barrier (BBB), which is composed of cerebral endothelial cells, astrocyte end-feet, and pericytes. Since the BBB regulates the homeostasis of central nervous system (CNS), the maintenance of the BBB is important for CNS function. The disruption of the BBB may result in many brain disorders including brain tumors. However, the molecular mechanism of BBB formation and maintenance is poorly understood. Here, we summarize recent advances in the role of oxygen tension and growth factors on BBB development and maintenance, and in BBB dysfunction related with brain tumors.

• Biomolecules & Therapeutics
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• 제10권2호
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• pp.99-103
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• 2002

Taurine has a neuroprotective action from oxidative stress in neural cell. In the present study, we studied taurine transport under basal and stressed conditions in conditionally immortalized rat brain capillary endothelial cell line (TR-BBB13) in vitro. The uptake of[$^3{H}$]taurine in the TR-BBB13 was increased by time-dependently and dependent on both Na$^{+}$ and Cl/ sup -/. Furthermore, $\beta$-alanine strongly inhibited the uptake of [TEX>$^3{H}$]taurine in the TR-BBB13. To study the effcts of oxidative stress on taurine transport, we used diethyl maleate (DEM) and lipopolysccharide (LPS). Diethyl maleate (DEM, $300\Mu\textrm{M}$) significantly reduced uptake of [TEX>$^3{H}$]taurine by time-dependently until 8 hr exposure in TR-BBB 13. But, the [TEX>$^3{H}$]taurine uptake was not changed by lipopolysccharide (LPS, 10 ng/ml) in TR-BBB13.3.

• 생명과학회지
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• 제32권7호
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• pp.550-566
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• 2022

뇌졸중은 세계적으로 사망과 장기간인 신체적, 인지적 장애의 주요 원인들 중 하나이며, 매년 약 1,500만명의 사람들에게 영향을 미친다. 뇌졸중의 병태 생리학적 과정은 다수의 사건들이 관여하는 복잡한 과정으로, 그 중 혈액-뇌 장벽(blood-brain barrier: BBB)의 붕괴는 허혈성 뇌손상의 진행에 크게 기여하는 것으로 알려져 있다. 따라서 BBB 붕괴는 뇌졸중의 특징으로 인식되므로 허혈성 뇌졸중에서 BBB 기능 장애를 보호할 수 있는 새로운 치료 전략을 개발하는 것이 뇌졸중 치료에 매우 중요하다. 전통한약은 천연물로 구성되어 있으며, 이는 뇌졸중 치료약 개발을 위한 유망한 원천이 될 수 있다. 실제로 여러 연구에서 뇌졸중에 대한 한의학의 효능이 밝혀져 허혈성 뇌졸중에 대한 한의학적 치료 가치가 부각되고 있다. 본 리뷰에서는 허혈성 뇌졸중으로 인한 BBB 붕괴에 대한 전통적인 한의학의 처방, 탕약, 약재 및 활성 성분의 개선효과에 관한 현재 정보와 기본 메커니즘을 요약 정리하였다. 이러한 연구가 한의학의 신경보호 효과에 대한 추가 조사를 촉진하고 뇌졸중 환자에 대한 한방유래의 임상시험 시행을 활성화하는데 도움이 되기를 기대한다.