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A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability

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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.

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Acknowledgments

This study was supported by National Institute of Health (NIH) Grant R01 NS063011 (to M.S.B.).

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Authors and Affiliations

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

    Do-Geun Kim & Margaret S. Bynoe

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  1. Do-Geun Kim
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  2. Margaret S. Bynoe
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Correspondence to Margaret S. Bynoe.

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Kim, DG., Bynoe, M.S. A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability. Mol Neurobiol 52, 664–678 (2015). https://doi.org/10.1007/s12035-014-8879-2

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  • DOI: https://doi.org/10.1007/s12035-014-8879-2

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