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A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability

Significance Statement

Significance Statement As the center for cognition and learning, and the master regulator of motor and autonomic function, the brain environment must be tightly controlled to maintain its homeostasis. Thus, the brain is separated both physically and physiologically from the peripheral circulation to protect it from harmful interactions such as toxins from the blood, and to maintain its strict ionic composition. The physical separation of the brain from the blood is achieved by the blood brain barrier (BBB), which is composed of a single layer of endothelial cells that coats the central nervous system (CNS) vasculature and is sealed off by tight and adherens junction proteins. The physiological separation of the brain from the blood circulation is also achieved by specialized brain endothelial cells equipped with efflux and influx transporters that selectively allow passage of substances (such as glucose) needed for proper brain function while excluding others. However, the very restrictive nature of the BBB hinders the delivery of drugs into the brain to treat neurological diseases ranging from brain tumors to Alzheimer’s disease. Many effective drugs are available to treat these diseases but their efficacy cannot be realized due to their inability to penetrate the BBB. With increased life expectancy that coincides with increased neurological diseases such as Alzheimer’s, the need to safely and effectively deliver therapy to the brain is becoming monumental. In this study, we demonstrated that activation of adenosine receptors (ARs) expressed on primary human brain endothelial cells increases the permeability of a human primary brain endothelial BBB model to drugs that do not penetrate the BBB. We demonstrate that, Lexiscan, an FDA approved A2A AR agonist rapidly and potently increase BBB permeability to passage of human T cells and the chemotherpeutic drug, Gemcitabine that do not normally penetrate the BBB. Importantly, AR increase in BBB permeability is reversible and is mediated by Rho-GTPase pathway, with subsequent disruption of tight and adherens juction proteins. These studies suggest that similar to our observation in mice, adenosine AR signaling controls BBB permeability in humans. We conclude that AR-mediated permeability of the BBB is an endogenous mechanism that has strong translational potential as a viable drug delivery technology with precise time-dependent delivery of drugs to the brain to treat human CNS diseases.


Figure 1 Legend: Primary human brain endothelial cells express A2A adenosine receptor and CD73 which generates adenosine.

A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability-	- Global Medical Discovery












Figure 2 Legend: Decrease in adherens junction molecule upon treatment with the A2A adenosine receptor agonist, Lexiscan.

A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability -- Global Medical Discovery













Figure Legend 3: Lexiscan-induced permeablization of human in vitro BBB increased extravasation of (A) FITC-Dextran and (B), the chemotherapeutic, Gemcitabine, resulting in increased glioma cell death from 15 to 30 minutes.

-	- Global Medical Discovery







Journal Reference

Kim DG, Bynoe MS. Mol Neurobiol. 2014 Sep 28.

Department of Microbiology and Immunology, Cornell University, College of Veterinary Medicine, Ithaca, NY, 14853, USA.


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.

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