TY - JOUR
T1 - Quantitative proteomics-based blood-brain barrier study
AU - Uchida, Yasuo
N1 - Funding Information:
The studies in this review were supported in part by Grants-in-Aids from the Japanese Society for the Promotion of Science (JSPS) for Young Scientists (A) [KAKENHI: 16H06218], Fostering Joint International Research (A) [KAKENHI: 18KK0446], Scientific Research (B) [KAKENHI: 20H03399], and Challenging Researches (Exploratory) [KAKENHI:
Funding Information:
also supported in part by Grants-in-Aids from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) for Scientific Researches on Innovative Areas [KAKENHI: 18H04534, 20H04690 and 20H05495], and from Mochida Memorial Foundation and Uehara Memorial Foundation.
Publisher Copyright:
© 2021 The Pharmaceutical Society of Japan.
PY - 2021
Y1 - 2021
N2 - From the viewpoint of drug discovery, it is an important issue to elucidate the drug permeability at the human central nervous system (CNS) barriers and the molecular mechanisms in the cells forming CNS barriers especially during CNS diseases. I introduced quantitative proteomics techniques into the blood-brain barrier (BBB) study, then quantitatively investigated the transport system at the human BBB and clarified the quantitative differences in protein expression levels and functions of transporters and receptors between animals and humans, or in vitro and in vivo. Based on the difference in the absolute expression level of transporters between in vitro and in vivo, I demonstrated that the drug efflux activity of P-glycoprotein (P-gp) at in vivo BBB can be accurately reconstructed from the in vitro system, not only in mouse models but also monkeys similar to humans and pathological conditions. Furthermore, I discovered Claudin-11 as another tight junction molecule expressed at the CNS barriers, and clarified that it contributes to the disruption of the CNS barriers in multiple sclerosis. Furthermore, it was also elucidated that the P-gp dysfunction causes excessive brain entry of glucocorticoid which causes a nerve damage in cerebral infarct, and it can be suppressed by targeting Abl/Src kinases. These suggest that targeting the tight junctions and transporters, which are important molecules at the CNS barriers, would potentially lead to the treatment of CNS diseases. In this review, I would like to introduce a new CNS barrier study opened by quantitative proteomics research.
AB - From the viewpoint of drug discovery, it is an important issue to elucidate the drug permeability at the human central nervous system (CNS) barriers and the molecular mechanisms in the cells forming CNS barriers especially during CNS diseases. I introduced quantitative proteomics techniques into the blood-brain barrier (BBB) study, then quantitatively investigated the transport system at the human BBB and clarified the quantitative differences in protein expression levels and functions of transporters and receptors between animals and humans, or in vitro and in vivo. Based on the difference in the absolute expression level of transporters between in vitro and in vivo, I demonstrated that the drug efflux activity of P-glycoprotein (P-gp) at in vivo BBB can be accurately reconstructed from the in vitro system, not only in mouse models but also monkeys similar to humans and pathological conditions. Furthermore, I discovered Claudin-11 as another tight junction molecule expressed at the CNS barriers, and clarified that it contributes to the disruption of the CNS barriers in multiple sclerosis. Furthermore, it was also elucidated that the P-gp dysfunction causes excessive brain entry of glucocorticoid which causes a nerve damage in cerebral infarct, and it can be suppressed by targeting Abl/Src kinases. These suggest that targeting the tight junctions and transporters, which are important molecules at the CNS barriers, would potentially lead to the treatment of CNS diseases. In this review, I would like to introduce a new CNS barrier study opened by quantitative proteomics research.
KW - Blood-brain barrier
KW - Claudin-11
KW - In vitro-to-in vivo reconstruction (IVIVR)
KW - P-glycoprotein (P-gp)
KW - Pharmacoproteomics (PPx)
KW - Quantitative targeted absolute proteomics (qTAP)
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U2 - 10.1248/BPB.B21-00001
DO - 10.1248/BPB.B21-00001
M3 - Review article
C2 - 33790097
AN - SCOPUS:85103745417
VL - 44
SP - 465
EP - 473
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
SN - 0918-6158
IS - 4
ER -