• Proceedings of the PSK Conference
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• 2003.04a
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• pp.200.1-200.1
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• 2003

The purpose of this study is to examine whether an brain to blood efflux system for taurine is present on the blood-brain barrier (BBB) or not and this efflux transport system is regulated by CNS cell damage with oxidative stress agent such as diethyl maleate (DEM) or tumor necrosis factor-a (TNF-${\alpha}$), by using the brain efflux index (BEI) method. The brain efflux index value is defined as the relative amount of test compound efflux from cerebrum compared with that of a reference compound, [$\^$14/C] carboxyinulin, which has limited BBB permeability. (omitted)

• 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.

• Journal of Korean Neurosurgical Society
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• v.30 no.12
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• pp.1430-1434
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• 2001

The authors present a case of brain abscess in a patient with primary mucociliary transport failure. Primary mucociliary transport failure is unfamiliar term to neurosurgeon. It encompasses three hereditary disorders, that is, primary ciliary dyskinesia, cystic fibrosis and Young's syndrome. Clinical manifestations in these disorders appear to overlap each other, e.g., male infertility and chronic sinopulmonary infections. These are characterized by ciliary dysfunction or abnormality of mucus secretion therefore recurrent infection occurs in organs containing the mucociliary transport system. Major causes of non-traumatic brain abscess are sinusitis and pulmonary infection. So the possibility of brain abscess is much higher if mucociliary transport failure exists. Especially, young patients who have brain abscess coexisting with chronic sinopulmonary infection should be considered primary mucociliary transport failure.

• 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.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.11a
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• pp.107-107
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• 2003

The purpose of this study is to examine that the efflux transport system for choline from brain to blood is present at the blood-brain barrier (BBB) using brain efflux index (BEI) method. ［$^3$H］Choline was microinjected into parietal cortex area 2 (Par2) region of rat brain, and was eliminated from the brain with an apparent elimination half life of 45 min. The BBB efflux clearance of ［$^3$H］choline was 0.12 $m\ell$/min/g brain, which was calculated from the efflux rate constant (1.5${\times}$10$\^$-2/ min$\^$-1/) and the distribution volume in the brain slice (8.1 $m\ell$/g brain). This process was saturable and significantly inhibited by various organic cationic compounds including hemicholinium-3, tetraethylammonium chloride (TEA) and verapamil, by antioxidant, ${\alpha}$-phenyl-n-tert-butyl nitrone (PBN), and by Alzheimer's disease therapeutics, such as acetyl $\ell$-carnitine and tacrine. In conclusion, this finding is the first direct in vivo evidence that choline is transported from brain to the blood across the BBB via a carrier-mediated efflux transport process.

• 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 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.

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.165-172
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• 1999

In the present work , the transport mechanism of a capsaicin derivative, DA-5018, through blood-brain barrier (BBB) has been investigated to evaluate the feasibility of potential drug development. The result of pharmacokinetic parameters obtained from the intravenous injection of plasma volume marker,$[3^H]RSA$ and $[{14}^C]DA-5018$, indicated that both AUC, area under the plasma concentration curve and VD, volume of distribution in brain of $[3^H]RSA$ agreed with those reported ($1620{\pm}10 $percentage injected dose minute per milliliter (%IDmin/ml) and $12.0{\pm}0.1{\mu}l/g$, respectively). Elimination half-life and AUC of $[{14}^C]DA-5018$is corrected by the PHLC analysis, 19.6$\pm$1.2 min and 7.69$\pm$0.85% IDmin/ml, respectively. The metabolic rate of $[{14}^C]DA-5018$was very rapid. The blood-brain barrier permeability surface area (PS) product of $[{14}^C]DA-5018$ was calculated to be 0.24$\pm$0.05 $\mu$l/min/g. The result of internal carotid artery perfusion and capillary depletion suggested that [14C]DA-5018 pass through BBB with the time increasingly. Investigation of transport mechanism of $[{14}^C]DA-5018$ using agonist and antagonist suggested that vanilloid (capsaicin) receptor did not exist in the BBB, and nutrient carrier system in the BBB has no effect on the transport of DA-5018. In conclusion, despite the fact that penetration of DA-5018 through BBB is significant, the intact drug found in the brain tissue is small because of a rapid metabolism. Therefore, for the central analgesic effect of DA-5018, the method to increase the metabolic stability in plasma and the brain permeability should be considered.

• 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.

• BMB Reports
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• v.43 no.5
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• pp.344-348
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• 2010

Messenger ribonucleoprotein particles (mRNPs) are used to transport mRNAs along neuronal dendrites to their site of translation. Staufen2 is an mRNA-binding protein expressed in the cell bodies and cellular processes of different brain cells. It is notably involved in the transport of dendritic mRNAs along microtubules. Its knockdown expression was shown to change spine morphology and impair synaptic functions. However, the identity of Staufen2-bound mRNAs in brain cells is still completely unknown. As a mean to identify these mRNAs, we immunoprecipitated Staufen2-containing mRNPs from embryonic rat brains and used a genome wide approach to identify Staufen2-associated mRNAs. The genome wide approach identified 1780 mRNAs in Staufen2-containing mRNPs that code for proteins involved in cellular processes such as post-translational protein modifications, RNA metabolism, intracellular transport and translation. These results represent an additional and important step in the characterization of Staufen2- mediated neuronal functions in rat brains.