• Top page
  • Timetable
  • Per session
  • Per presentation
  • How to
  • Meeting Planner



Recent progress in the regulation of blood-brain barrier (BBB)

開催日 2014/9/13
時間 15:00 - 17:00
会場 Room E(301)
Chairperson(s) 寺崎 哲也 / Tetsuya Terasaki (東北大学大学院薬学研究科 / Department of Biochemical Pharmacology and Therapeutics, Tohoku University, Japan)
横田 隆徳 / Takanori Yokota (東京医科歯科大学 大学院医歯学総合研究科 脳神経病態学分野 / Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan)

Overview: Recent Progress of the BBB Research

  • S3-E-2-4
  • 寺崎 哲也 / Tetsuya Terasaki:1 
  • 1:東北大学 / Tohoku University, Japan 

The blood-brain barrier (BBB), which is formed by complex tight junctions of the brain capillary endothelial cells, segregates the brain interstitial fluid from the circulating blood. Recent progress of the BBB research has changed the barrier concept from a classical static wall to a dynamic interface exchanging compounds across the brain capillary endothelial cells. For example, Glucose Transporter 1 (GLUT1) and Large Neutral Amino Acid Transporter 1 (LAT1) act as the blood-to-brain influx transport systems supplying glucose and large neutral amino acid to the brain, respectively. Several drugs and organic anions are pumped out to the circulating blood via Multidrug Resistance Protein 1 (MDR1), Breast Cancer Resistant Protein (BCRP) and Multidrug Resistance-Associated Protein 4 (MRP4) at the luminal membrane of the brain capillary endothelial cells. Drugs recognized by these transporters have significant unbound concentration gradient between the brain interstitial fluid and the blood, which is one of the most critical issues limiting the CNS drug discovery and development. The BBB research has been facilitated by the development of novel in vivo experimental methods, e.g., brain uptake index and brain efflux index together with in vitro model system such as isolated brain capillaries, conditionally immortalized cultured cell line and immortalized cell line in human (D3). For the rational and efficient drug discovery and development, understanding of the human BBB transport system and its regulation mechanism are very important. It is also an important subject to clarify interspecies differences of the BBB transport mechanism and activity in a quantitative manner. Recently, we have developed a protein quantification method by LC-MS/MS combined with in silico peptide selection criteria. Employing this method, we have clarified the absolute protein expression amount in the human BBB such as MDR1, BCRP, MRP4 together with those of mice, rat, marmoset and cynomolgous monkey. Moreover, in vivo mdr1a efflux activity of the mouse BBB was succeeded to re-construct by the integration of mdr1a protein expression amount in the mouse brain capillaries and the activity of mdr1a for 11 drugs, e.g., quinidine, digoxin and verapamil. Moreover, we succeeded to re-construct in vivo efflux activity of mdr1a in the epileptic mouse models.

Copyright © Neuroscience2014. All Right Reserved.