• Biomolecules & Therapeutics
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• v.27 no.3
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• pp.290-301
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• 2019

Paeonol has neuroprotective function, which could be useful for improving central nervous system disorder. The purpose of this study was to characterize the functional mechanism involved in brain transport of paeonol through blood-brain barrier (BBB). Brain transport of paeonol was characterized by internal carotid artery perfusion (ICAP), carotid artery single injection technique (brain uptake index, BUI) and intravenous (IV) injection technique in vivo. The transport mechanism of paeonol was examined using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) as an in vitro model of BBB. Brain volume of distribution (VD) of [$^3H$]paeonol in rat brain was about 6-fold higher than that of [$^{14}C$]sucrose, the vascular space marker of BBB. The uptake of [$^3H$]paeonol was concentration-dependent. Brain volume of distribution of paeonol and BUI as in vivo and inhibition of analog as in vitro studies presented significant reduction effect in the presence of unlabeled lipophilic compounds such as paeonol, imperatorin, diphenhydramine, pyrilamine, tramadol and ALC during the uptake of [$^3H$]paeonol. In addition, the uptake significantly decreased and increased at the acidic and alkaline pH in both extracellular and intracellular study, respectively. In the presence of metabolic inhibitor, the uptake reduced significantly but not affected by sodium free or membrane potential disruption. Similarly, paeonol uptake was not affected on OCTN2 or rPMAT siRNA transfection BBB cells. Interestingly. Paeonol is actively transported from the blood to brain across the BBB by a carrier mediated transporter system.

• Science of Emotion and Sensibility
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• v.11 no.4
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• pp.565-574
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• 2008

Functions of human brain including sensibility and emotion may be affected by drugs mediated by the blood-brain barrier (BBB). The present study was performed to evaluate whether injection route, volume and concentration of mannitol could alter the degree of disruption of the BBB. Under urethane anesthesia, female Sprague-Dawley rats were infused with 20% mannitol into the right internal carotid artery (ICA). In the other group, intravenous injection of mannitol through the femoral vein was performed. Evans blue(EB) dye was used as a marker of BBB disruption. When mannitol was injected via the ICA, the content of EB dye in the ipsilateral hemisphere was markedly increased. However, the content of EB in the brain was not increased when mannitol was injected via the femoral vein, even though the volume or concentration of mannitol was increased. These results suggest that the BBB was disrupted only through ICA injection route and this may provide a useful strategy for transient opening of the BBB to control the functions of human brain.

• Journal of Pharmaceutical Investigation
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• v.20 no.4
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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.

• YAKHAK HOEJI
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• v.46 no.2
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• pp.124-128
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• 2002

The nitrone-based free radical trapping reagent, $\alpha$-phenyl-n-tert-butyl nitrone (PBN) has been proposed as therapeutic agent for stroke. We used this for model drug of development of new drug for neuroprotection. The purpose of this study was to evaluate the blood-brain barrier (BBB) permeability of PBN in Sprague-Dawly (SD) rats. The BBB transport of PBN was investigated in SD rats using internal carotid artery perfusion (ICAP) method at a rate of 4 mι/min for 15 second. We also obtained pharmacokinetic parameters of PBN using single intravenous injection technique. When we estimated BBB permeability of PBN with ICAP method, the brain volume of distribution of PBN was 60.0 $\pm$ 12.0 $\mu\textrm{g}$/ι. The brain uptake of PBN after IV injection at 120 min was 0.15 $\pm$ 0.01%ID/g. The PBN was transported to the brain through the BBB well in rats, because PBN is small molecule (MW 177) and lipid-soluble (log P 1.23) compound.

• YAKHAK HOEJI
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• v.47 no.4
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• pp.224-229
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• 2003

We have investigated the transport characteristics of synthetic antioxidant and free radical scavenger, $\alpha$-phenyl-n-tert-butyl nitrone (PBN) at the blood-brain barrier (BBB) by in vitro uptake study in conditionally immortalized rat brain capillary endothelial cell line (TR-BBB). Also, the efflux of PBN from brain to blood is estimated using the brain efflux index (BEI) method. Choline is a charged organic cation, including nitrogen-methyl group and shows the carrier-mediated distribution to the brain. [$^3$H]Choline uptake by TR-BBB cells was significantly inhibited by PBN with $IC_{50}$/ of 1.2 mM, which appears to be due to similar structures between choline and PBN. And, PBN was microinjected into Par2 of the rat brain by BEI method, and was eliminated from the brain with an apparent elimination half-life of about 2 min. Also, [$^3$H]choline efflux was significantly inhibited by PBN using BEI method. In conclusion, the efflux transport of PBN takes place across the BBB and PBN may be transported into the brain and eliminated from the brain by BBB choline transporter.

• Journal of Korean Neurosurgical Society
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• v.62 no.1
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• pp.10-26
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• 2019

Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging new technology with considerable potential to treat various neurological diseases. With refinement of ultrasound transducer technology and integration with magnetic resonance imaging guidance, transcranial sonication of precise cerebral targets has become a therapeutic option. Intensity is a key determinant of ultrasound effects. High-intensity focused ultrasound can produce targeted lesions via thermal ablation of tissue. MRgFUS-mediated stereotactic ablation is non-invasive, incision-free, and confers immediate therapeutic effects. Since the US Food and Drug Administration approval of MRgFUS in 2016 for unilateral thalamotomy in medication-refractory essential tremor, studies on novel indications such as Parkinson's disease, psychiatric disease, and brain tumors are underway. MRgFUS is also used in the context of blood-brain barrier (BBB) opening at low intensities, in combination with intravenously-administered microbubbles. Preclinical studies show that MRgFUS-mediated BBB opening safely enhances the delivery of targeted chemotherapeutic agents to the brain and improves tumor control as well as survival. In addition, BBB opening has been shown to activate the innate immune system in animal models of Alzheimer's disease. Amyloid plaque clearance and promotion of neurogenesis in these studies suggest that MRgFUS-mediated BBB opening may be a new paradigm for neurodegenerative disease treatment in the future. Here, we review the current status of preclinical and clinical trials of MRgFUS-mediated thermal ablation and BBB opening, described their mechanisms of action, and discuss future prospects.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.90-91
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• 2002

The brain is unique as target for drug delivery because it is an organ with the greatest blood supply, which receives about 20% of the cardiac output in humans and is highly restricted by a tight vascular barrier, the blood-brain barrier (BBB). Since the BBB forms the interface between blood and brain, the biology of the BBB plays a role in multiple disciplines other than pharmacology, physiology, pathology and neurosciences. (omitted)

• Proceedings of the Korean Society of Applied Pharmacology
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• 1998.11a
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• pp.192-192
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• 1998

The blood - brain barrier (BBB) expresses high concentrations of transferrin receptor, and it was revealed that anti-transferrin receptor mouse monoclonal antibody (OX26) undergoes transcytosis through the BBB. This property allows the OX26 to serve as a brain drug delivery vector. In an attempt to produce broadly useful targeting agents, genetic engineering and expression techniques have been used to produce antibody-avidin (AV) fusion protein (OX26 IgG3C$\_$H/3-AV). In the present study we estimated the BBB permeability and stability of genetically engineered vector.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.11a
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• pp.106-106
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• 2003

Choline serves critical roles in the CNS both as a precursor of neurotransmitter and as an essential component of membrane phospholipids. The long-term maintenance of brain choline concentration is dependent on choline transport across the blood-brain barrier (BBB), And, we examined to elucidate the characteristics of transport of choline across the BBB using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) in vitro. The ［$^3$H］choline in TR - BBB was increased by time dependently, but independent on Na$\^$＋/, and the transport process is saturable with Michaelis-Menten constrant, Km of about 26 ${\mu}$M. The uptake of ［$^3$H］choline is susceptible for inhibition by various organic cationic compounds including hemicholinium-3, tetraethylammonium chloride (TEA) and $\ell$-carnitine. Also, we investigated the relationship of transport of choline and cationic drugs. The uptake of ［$^3$H］choline is inhibited by antioxidant, a-phenyl-n-tert-butyl nitrone (PBN) with IC$\sub$50/ of 1.2 mM. and by Alzheimer's disease therapeutics, such as acetyl $\ell$-carnitine, tacrine and donepezil. Also, choline uptake presented competitive inhibition with PBN, donepezil and acetyl $\ell$-carnitine in Lineweaver-Burk plot. In conclusion, TR-BBB cells express a saturable transport system for uptake of choline, and several cationic drugs may be transported into the brain by BBB choline transporter.

• Biomolecules & Therapeutics
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• v.16 no.1
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• pp.14-20
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• 2008

In the present study, we examined how the transport of choline is regulated at the blood-brain barrier (BBB) under the central nervous system (CNS) cellular damages by oxidative stress using a conditionally immortalized rat brain capillary endothelial cells (TR-BBB), in vitro the BBB model. It was also tested whether the choline uptake is influenced by membrane potential, extracellular pH, protonophore (FCCP) and amiloride in TR-BBB cells. In result, $[^3H]choline$ uptake was inhibited by FCCP and dependent on extracellular pH. The treatment of TR-BBB cells with 20 ng/mL tumor necrosis $factor-{\alpha}$ $(TNF-{\alpha})$, 10 ng/mL lipopolysaccharide (LPS), 100 ${\mu}M$ diethyl maleate (DEM) and 100 ${\mu}M$ glutamate resulted in 3.0-fold, 2.6-fold, 1.8-fold and 2.0-fold increases of $[^3H]choline$ uptake at the respective peak time, respectively. In contrast, hydrogen peroxide and raffinose did not show any significant effects on choline uptake. In addition, choline efflux was significantly inhibited by $TNF-{\alpha}$, LPS and DEM producing cell damage states. In conclusion, the influx and efflux transport system for choline existed in TR-BBB cell line and this process was affected by several oxidative stress inducing agents.