A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability

Mol Neurobiol. 2015 Aug;52(1):664-78. doi: 10.1007/s12035-014-8879-2. Epub 2014 Sep 28.

Abstract

The blood-brain barrier (BBB) symbolically represents the gateway to the central nervous system. It is a single layer of specialized endothelial cells that coats the central nervous system (CNS) vasculature and physically separates the brain environment from the blood constituents to maintain the homeostasis of the CNS. However, this protective measure is a hindrance to the delivery of therapeutics to treat neurological diseases. Here, we show that activation of A2A adenosine receptor (AR) with an FDA-approved agonist potently permeabilizes an in vitro primary human BBB (hBBB) to the passage of chemotherapeutic drugs and T cells. T cell migration under AR signaling occurs primarily by paracellular transendothelial route. Permeabilization of the hBBB is rapid, time-dependent, and reversible and is mediated by morphological changes in actin-cytoskeletal reorganization induced by RhoA signaling and a potent downregulation of claudin-5 and VE-cadherin. Moreover, the kinetics of BBB permeability in mice closely overlaps with the permeability kinetics of the hBBB. These data suggest that activation of A2A AR is an endogenous mechanism that may be used for CNS drug delivery in human.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine A2 Receptor Agonists / pharmacology
  • Adherens Junctions / drug effects
  • Adherens Junctions / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Blood-Brain Barrier / metabolism*
  • Cell Death / drug effects
  • Cell Line
  • Cell Membrane Permeability* / drug effects
  • Cell Movement / drug effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Down-Regulation / drug effects
  • Electric Impedance
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism
  • Focal Adhesions / drug effects
  • Focal Adhesions / metabolism
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology
  • Humans
  • Jurkat Cells
  • Mice, Inbred C57BL
  • Phosphorylation / drug effects
  • Receptors, Adenosine A2 / metabolism*
  • Signal Transduction / drug effects
  • Stress Fibers / drug effects
  • Stress Fibers / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Adenosine A2 Receptor Agonists
  • Antineoplastic Agents
  • Receptors, Adenosine A2
  • Deoxycytidine
  • gemcitabine
  • rhoA GTP-Binding Protein