Retrieval of blood-brain barrier transport function towards dementia prevention

• Project/Area Number: 25670067
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Tohoku University
• Principal Investigator: Tachikawa Masanori 東北大学, 薬学研究科(研究院), 准教授 (00401810)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 血液脳関門 / 認知症 / トランスポーター / 輸送タンパク質 / 定量プロテオミクス / チャネル / 脳血管障害 / 輸送系 / 神経活動 / 輸送 / 活性化

Outline of Final Research Achievements

The purpose of the present research was to clarify the blood-brain barrier (BBB) transport system for dementia-preventing substances and the changes in transport functions and transporter expression levels under brain vascular disease conditions. A transport protein of docosahexaenoic acid (DHA) was identified in the human brain endothelial cells (hCMEC/D3 cells). The DHA uptake by hCMEC/D3 cells was enhanced by an activating factor. In vitro study with the transwell culture of hCMEC/D3 cells indicated that ischemia-related changes in the BBB transport involved the basal channel opening. Quantitative targeted absolute proteomics revealed the changes in the expression profiles of transporter proteins at the BBB in mouse models of brain vascular disorders. These results could provide the basis of dementia prevention by the retrieval of blood-brain barrier transport function.

Research Products

• [Journal Article] Pharmacological significance of prostaglandin E2 and D2 transport at the brain barriers. (2014)
  • Author(s): Tachikawa M, Hosoya K, Terasaki T
  • Journal Title: Adv Pharmacol Volume: 71 Pages: 337-360
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Involvement of insulin-degrading enzyme in insulin- and atrial natriuretic peptide-sensitive internalization of amyloid-β peptide in mouse brain capillary endothelial cells. (2014)
  • Author(s): Ito S, Ohtsuki S, Murata S, Katsukura Y, Suzuki H, Funaki M, Tachikawa M, Terasaki T
  • Journal Title: J Alzheimers Dis Volume: 38 Issue: 1 Pages: 185-200
  • DOI: 10.3233/jad-122077
  • Peer Reviewed
• [Journal Article] Pharmacokinetics of guanidinosuccinic acid in rat blood and cerebrospinal fluid. (2014)
  • Author(s): Kasai Y, Akanuma SI, Kubo Y, Tachikawa M, Hosoya K
  • Journal Title: Drug Metab Pharmacokinet Volume: 29 Pages: 97-100
  • NAID: 130004463342
  • Peer Reviewed
• [Journal Article] Quantitative atlas of blood-brain barrier transporters, receptors and tight junction proteins in rats and common marmoset. (2013)
  • Author(s): Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T
  • Journal Title: J Pharm Sci Volume: 102 Issue: 9 Pages: 3343-3355
  • DOI: 10.1002/jps.23575
  • Peer Reviewed
• [Journal Article] A Study Protocol for Quantitative Targeted Absolute Proteomics (QTAP) by LC-MS/MS: Application for Inter-Strain Differences in Protein Expression Levels of Transporters, Receptors, Claudin-5, and Marker Proteins at the Blood-Brain Barrier in ddY, FVB, and C57BL/6J mice. (2013)
  • Author(s): Y Uchida, M Tachikawa, W Obuchi, Y Hoshi, Y Tomioka, S Ohtsuki, T Terasaki
  • Journal Title: Fluids Barriers CNS Volume: 10 Issue: 1 Pages: 21-21
  • DOI: 10.1186/2045-8118-10-21
  • Peer Reviewed
• [Journal Article] Quantitative Targeted Absolute Proteomic Analysis of Transporters, Receptors and Junction Proteins for Validation of Human Cerebral Microvascular Endothelial Cell Line hCMEC/D3 as a Human Blood-Brain Barrier Model. (2012)
  • Author(s): Ohtsuki S
  • Journal Title: Mol Pharm Volume: 10 Issue: 1 Pages: 289-296
  • DOI: 10.1021/mp3004308
  • Peer Reviewed
• [Presentation] Pathological impact of hemichannels-mediated gateway on the brain barrier transport dynamics. (2015)
  • Author(s): Tachikawa T.
  • Organizer: Pharmaceutical Science Symposium 2015
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2015-11-16
  • Int'l Joint Research / Invited
• [Presentation] Impact of pannexin 1 and connexin 43 hemichannels on extracellular calcium-dependent transport dynamics in human brain capillary endothelial cells. (2015)
  • Author(s): Tachikawa M, Kaneko Y, Akaogi R, Uchida Y, Couraud PO, Terasaki T.
  • Organizer: Barcelona BioMed Conference, Blood Brain Barrier
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2015-11-02
  • Int'l Joint Research
• [Presentation] 血液脳関門ファーマコプロテオミクスに立脚した中枢疾患創薬の提言 (2015)
  • Author(s): 立川正憲、内田康雄、大槻純男、寺崎哲也
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-28
  • Invited
• [Presentation] Plasticity and robustness of the blood-brain-barrier transporters, channels, and receptors: a study of advanced quantitative targeted proteomics. (2014)
  • Author(s): Tachikawa M
  • Organizer: 19th North American ISSX/29th JSSX Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-10-21
  • Invited
• [Presentation] Dynamic plasticity of “Cluster of differentiation antigen” expressions at the inflammatory blood-brain barrier. (2014)
  • Author(s): Sato K, Tachikawa M, Uchida Y, Ohtsuki S, Terasaki T
  • Organizer: 19th North American ISSX/29th JSSX Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-10-19 – 2014-10-23
• [Presentation] Channels at the Barriers: A Non-Transporter-Mediated Gateway. (2014)
  • Author(s): Tachikawa M
  • Organizer: Gordon Research Conference, Barriers of the CNS
  • Place of Presentation: New London, USA
  • Year and Date: 2014-06-19
  • Invited
• [Book] Drug Delivery to the Brain ; Physiological Concepts, Methodologies and Approaches (2014)
  • Author(s): Tachikawa M, Uchida Y, Ohtsuki S, Terasaki T
  • Total Pages: 731
  • Publisher: Springer