• BMB Reports
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• v.55 no.5
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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.

• Journal of Korean Neurosurgical Society
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• v.66 no.2
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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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• v.23 no.1
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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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• v.52 no.2
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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.

• The Journal of the Acoustical Society of Korea
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• v.41 no.5
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• pp.564-569
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• 2022

Blood-Brain Barrier (BBB) is the brain protecting system blocking the inflow of harmful substances into brain parenchyma from brain blood vessel. However, the BBB has a negative effect on the treatment of various brain diseases such as Alzheimer's dementia or brain tumors because it also prevents drug delivery into brain parenchyma. To overcome this problem, a brain drug delivery technique using Focused Ultrasound (FUS) which allows BBB to be temporarily opened by inducing the acoustic cavitation effect of microbubbles has been developed. Thus far, various studies using the FUS technique has been conducted to improve drug delivery efficiency, and therefore, this paper discusses recently developed drug delivery technologies using the FUS-induced BBB opening.

• Biomolecules & Therapeutics
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• v.18 no.1
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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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• v.29 no.4
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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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• v.10 no.2
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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.

• Journal of Life Science
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• v.32 no.7
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• pp.550-566
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• 2022

Stroke is among the leading causes of death and long-term physical and cognitive disabilities worldwide, affecting an estimated 15 million people annually. The pathophysiological process of stroke is complicated by multiple and coordinated events. The breakdown of the blood-brain barrier (BBB) in people with stroke can significantly contribute to the development of ischemic brain injury. Therefore, BBB disruption is recognized as a hallmark of stroke; thus, it is important to develop novel therapeutic strategies that can protect against BBB dysfunction in ischemic stroke. Traditional medicines are composed of natural products, which represent a promising source of new ingredients for the development of conventional medicines. Indeed, several studies have shown the effectiveness of Korean medicine on stroke, highlighting the value of Korean medicinal treatment for ischemic stroke. This review summarizes the current information and underlying mechanisms regarding the ameliorating effects of the formula, decoction, herbs, and active components of traditional Korean medicine on cerebral ischemia-induced BBB disruption. These traditional medicines were shown to have protective effects on the BBB in many cellular and animal ischemia models of stroke, and experiments in various animal species, such as mice and rats. In addition, they showed brain-protective effects by protecting the BBB through the regulation of tight junction proteins and matrix metalloproteinase-9, reducing edema, neuroinflammation, and neuronal cell death. We hope that this review will help promote further investigation into the neuroprotective effects of traditional Korean medicines and stimulate the performance of clinical trials on Korean herbal medicine-derived drugs in patients with stroke.

• Archives of Pharmacal Research
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• v.28 no.4
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• pp.443-450
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• 2005

In the present study, we have characterized the choline transport system and examined the influence of various amine drugs on the choline transporter using a conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) in vitro. The cell-to-medium (C/M) ratio of $[^3{H}]choline$ in TR-BBB cells increased time-dependently. The initial uptake rate of $[^3{H}]choline$ was concentration-dependent with a Michaelis-Menten value, $K_{m}$, of $26.2\pm2.7{\mu}M$. The $[^3{H}]choline$ uptake into TR-BBB was $Na^{+}-independent$, but was membrane potential-dependent. The $[^3{H}]choline$ uptake was susceptible to inhibition by hemicholinium-3, and tetraethy-lammonium (TEA), which are organic cation transporter substrates. Also, the uptake of $[^3{H}]choline$ was competitively inhibited with $K_{i}$ values of $274 {\mu}M, 251 {\mu}M and 180 {\mu}M$ in the presence of donepezil hydrochloride, tacrine and $\alpha-phenyl-n-tert-butyl nitrone$ (PBN), respectively. These characteristics of choline transport are consistent with those of the organic cation transporter (OCT). OCT2 mRNA was expressed in TR-BBB cells, while the expression of OCT3 or choline transporter (CHT) was not detected. Accordingly, these results suggest that OCT2 is a candidate for choline transport at the BBB and may influence the BBB permeability of amine drugs.