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2001 Fiscal Year Final Research Report Summary

Evaluation of the blood-brain barrier based on the functional analysis of transporters using newly developed techniques.

Research Project

Project/Area Number 12557229
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionKANAZAWA UNIVERSITY

Principal Investigator

TAMAI Ikumi  Kanazawa University, Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (20155237)

Co-Investigator(Kenkyū-buntansha) SAI Yoshimichi  Kanazawa University, Graduate School, Associate Professor, 大学院・自然科学研究科, 助手 (40262589)
TSUJI Akira  Kanazawa University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (10019664)
Project Period (FY) 2000 – 2001
Keywordsblood-brain barrier / transporter / brain capillary indothelial cell / carnitine transporter / amino acid transporter / monocarboxylic acid transporter / astrocyte / coculture
Research Abstract

In the present study, we studied membrane transporters equippecd, in the brain capillary endothelial cells that are functional as the blood-brain barrier. Through this study, we found three new transporters that are expressed at the blood-brain barrier.
One of those transporters are monocarboxylic acid transporter MGT1, which tworks for uptake and/or efflux organic weak acids such as lactic acid, pyruvic acid and benzoic acid. The second transporter is neutral amino acid transporters LAT1 and LAT2. These two amino acid transporters work for the uptake of amino acids that are relatively hydrdphpbic and large molecules, including leucine, tyrosine and phenylalanine. These are also important for the brain livery of L-DOPA that is effective for perkinsonism. The third transporter is OCTN2that is callsified as the carnitine/organic cation transporter. OCTN2 is a Na^+-dependent carnitine transporter and works for the brain uptake of acetyl-L-carhitirie that is expected to be useful for Aitzhe … More imer's disease. On the other hand, brain efflux transporters that protect brain from the toxic xenobiotics. As the model drugs, H1-antagonist, ebastine and carebasitine and fluoroquinolone, grepafloxacine, was used in the present study. Generally, fluoroquinolonesand H1 antagonists exhibit adverse effects such as epilepsy and sedative effects, while the drugs studied in the present study do not show such adverse effects. We expected that these drugs might not have enough permeability across the blood-brain barrier, resulting in the insufficient delivery to the brain to cause unfavorable adverse effects. Varipus Kinds of studies on the BBB transport of these drugs demonstrated that there are at least two types of brain efflux transporters, including p-glycoproteih and anion exchange transporter, of which molecular identification remains to be succeeded.
All of these studies were performed by using various BBB-transport techniques. Especially, newly developed cell line RBEC1 that were derived from rat brain capillary endothelial cells was useful for the success of the present study. Furthermore, we challenged of the coculture of the endothelial cells and astrocytes in order to mimic the in vivo BBB. Although we partly succeeded to prepare the in vitro BBB model, further improvement will be essential for the efficient and complete model for the evaluation of blood-brain barrier transport. Less

  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Yasuto Kido: "Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier of rats using in vitro cultured cells and in vivo BUI studies"Pharmaceutical Research. 17. 55-62 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ikumi Tamai: "Blood-brain barrier transport of H1-antagonist ebastine and its metabolite cerebastine"Journal of Drug Targeting. 8. 383-393 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ikumi Tamai: "Limited distribution of new quinolone antibacterial agents into brain owing to multiple efflux transporters at blood -brain barrier"Journal of Pharmacology and Exprimental Therapeutics. 295. 146-152 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ikumi Tamai: "Transporter-mediated permeation of drug across the blood-brain barrier"Journal of Pharmaceutical Sciences. 89. 1371-1388 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 木戸康人: "血液脳関門の排出系"生体の科学. 52. 571-576 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 玉井郁巳: "神経疾患の薬物療法 -現状と将来-"Clinical Neuroscience. 19. 21-23 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yasuto Kido: "Functional relevance of carnitine transporter OCTN2 to brain distribution of L-carnitine and acetyl-L-carnitine across the blood-brain barrier"Journal of Neurochemistry. 79. 959-969 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yasuto Kido: "Molecular and functional identification of large neutral amino acid transporter LAT1 at the blood-brain barrier using rat cultured cells"Journal of Pharmacy and Pharmacology. 53. 497-503 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yasuto Kido: "Evaluation of blood-brain barrier transporters by co-culture of brain capillary encthelial cells with astrocytes"Drug Metabolism and Pharmacokinetics. 17・1. 34-41 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kido, Y., Tamai, I., Okamoto, M., Suzuki,F., Tsuji, A.: "Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier of rats using in vitro cultured cells and in vivo BUI studies"Pharm. Res.. 17. 55-62 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tamai, I., Kido, Y., Yamashita, J., Sai, Y., Tsuji, A.: "Blood-brain barrier transport of H1-antagonist ebastine and its metabolite carebastine"J. Drug Targeting.. 8. 383-393 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tamai, I., Yamashita, J., Kido, Y., Ohnari, A., Sai, Y., Shima, Y., Naruhashi, K., Koizumi, S., Tusji, A.: "Limited distribution of new quinolone antibacterial agents into brain owing to multiple efflux transporters at the blood-brainbarrier"J. Pharmacol. Exp. Ther.. 295. 146-152 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tamai, I., Tsuji, A.: "Transporter-mediated permeation of drugs across the blood-brain barrier"J. Pharm. Sci. 89. 1371-1388 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kido, Y., Sai, Y., Tamai, I., Tsuji.: "Efflux transport system at the blood-brain barrier"Seitai no kagaku (in Japanese). 52. 571-576 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tamai, I., Tsuji, A.: "ketsuekinokannmon toshinkeishikkan chiryoyaku"Clin. Neurosci.. 19. 21-23 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kido, Y., Tamai, I., Ohnari, A., Sai, Y., Kagami, T., Nezu, J., Nikaido, H., Hashimoto, N., Asano, M., Tsuji, A.: "Functional Relevance of Camitiue Transporter OCTN2 to Brain Distribution of L-Camitine and Acetyl-L-carnitine across the Blood-Brain Barrier"J. Neurochem.. 79. 959-969 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kido, Y., Tamai, I., Uchino, H., Suzuki, F., Sai, Y., Tsuji, A.: "Molecular and fimctiohal identification of large neutral amino acid transporter LAT 1 at the blood-brain barrier using rat cultured cells"J. Pharm. Pharmacol.. 53. 497-503 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kido, Y., Tamai, I., Nakanishi, T., Kagami, T., Hirosawa, I., Sai, Y., Tsuji, A.: "Evaluation of blood-brain barrier transporters by co-culture of brain capillary endothelial cells with astrocytes"Drug Metabol. Pharmacokin.. 17. 34-41 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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