Identification of Blood-Brain Barrier-Permeable Proteins Derived from a Peripheral Organ: In Vivo and in Vitro Evidence of Blood-to-Brain Transport of Creatine Kinase

Kazuki Sato, Masanori Tachikawa, Michitoshi Watanabe, Eisuke Miyauchi, Yasuo Uchida, Tetsuya Terasaki

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Certain proteins, such as inflammatory cytokines, that are released from injured or diseased organs are transported from the circulating blood through the blood-brain barrier (BBB) into the brain and contribute to the pathogenesis of related central nervous system dysfunctions. However, little is known about the protein transport mechanisms involved in the central nervous system dysfunctions. The aims of the present study were to identify BBB-permeable protein(s) derived from liver and to clarify their transport characteristics at the BBB. After administration of biotin-labeled liver cytosolic protein fraction to mice in vivo, we identified 9 biotin-labeled proteins in the brain. Among them, we focused here on creatine kinase (CK). In vitro uptake studies with human brain microvessel endothelial cells (hCMEC/D3 cells) showed preferential uptake of muscle-type CK (CK-MM) compared with brain-type CK (CK-BB) at the BBB. Integration plot analysis revealed that CK-MM readily penetrated into brain parenchyma from the circulating blood across the BBB. The uptake of CK-MM by hCMEC/D3 cells was decreased at 4 °C and in the presence of clathrin- and caveolin-dependent endocytosis inhibitors. These results indicate that entry of CK into the brain is mediated by a transport system(s) at the BBB.

Original languageEnglish
Pages (from-to)247-257
Number of pages11
JournalMolecular pharmaceutics
Volume16
Issue number1
DOIs
Publication statusPublished - 2019 Jan 7

Keywords

  • blood-brain barrier
  • blood-brain barrier-permeable protein
  • comprehensive quantitative proteomics
  • creatine kinase
  • peripheral-to-CNS communication

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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