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Review
. 2015 Sep 2:12:20.
doi: 10.1186/s12987-015-0017-7.

Adenosine receptor signaling: a key to opening the blood-brain door

Margaret S Bynoe  1 , Christophe Viret  2 , Angela Yan  3 , Do-Geun Kim  4
Affiliations
Review

Adenosine receptor signaling: a key to opening the blood-brain door

Margaret S Bynoe et al. Fluids Barriers CNS. .

Abstract

The aim of this review is to outline evidence that adenosine receptor (AR) activation can modulate blood-brain barrier (BBB) permeability and the implications for disease states and drug delivery. Barriers of the central nervous system (CNS) constitute a protective and regulatory interface between the CNS and the rest of the organism. Such barriers allow for the maintenance of the homeostasis of the CNS milieu. Among them, the BBB is a highly efficient permeability barrier that separates the brain micro-environment from the circulating blood. It is made up of tight junction-connected endothelial cells with specialized transporters to selectively control the passage of nutrients required for neural homeostasis and function, while preventing the entry of neurotoxic factors. The identification of cellular and molecular mechanisms involved in the development and function of CNS barriers is required for a better understanding of CNS homeostasis in both physiological and pathological settings. It has long been recognized that the endogenous purine nucleoside adenosine is a potent modulator of a large number of neurological functions. More recently, experimental studies conducted with human/mouse brain primary endothelial cells as well as with mouse models, indicate that adenosine markedly regulates BBB permeability. Extracellular adenosine, which is efficiently generated through the catabolism of ATP via the CD39/CD73 ecto-nucleotidase axis, promotes BBB permeability by signaling through A1 and A2A ARs expressed on BBB cells. In line with this hypothesis, induction of AR signaling by selective agonists efficiently augments BBB permeability in a transient manner and promotes the entry of macromolecules into the CNS. Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain. Thus, AR modulation of the BBB appears as a system susceptible to tighten as well as to permeabilize the BBB. Collectively, these findings point to AR manipulation as a pertinent avenue of research for novel strategies aiming at efficiently delivering therapeutic drugs/cells into the CNS, or at restricting the entry of inflammatory immune cells into the brain in some diseases such as multiple sclerosis.

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Figures

Fig. 1
Fig. 1
Schematic of blood brain barrier (BBB) structure and the neurovascular unit (NVU). The brain vasculature is lined with a single layer of endothelial cells that is tightly sealed by tight and adherens junction molecules. It is further insulated by pericytes and astrocytic endfoot processes and in total are referred to as the NVU. Efflux and influx transporters expressed on BBB endothelial cells selectively allow the entry or exit of molecules into or out of the brain
Fig. 2
Fig. 2
Adenosine is a purine nucleoside produced by many different organs throughout the body. Extracellular adenosine is a primordial molecule that is produced by many cell types in the body. These include heart, lung, gut, brain and immune cells. Adenosine produced by these cells can in turn act on the producing cells or on adjacent cells to modulate function. Extracellular adenosine is produced from ATP released in the extracellular environment upon cell damage and is converted to ADP and AMP by CD39. AMP is further converted to adenosine by CD73. Extracellular adenosine binds to its receptors expressed on the same cell or adjacent cells to mediate its function. Adenosine is rapidly degraded to inosine by adenosine deaminase
Fig. 3
Fig. 3
Cells of the central nervous system (CNS) not only produce adenosine but are also regulated by adenosine. Cells of the CNS, such as astrocytes, microglia, pericytes and neuronal cells can produce adenosine or their activity/function is regulated by adenosine. Adenosine regulates the blood brain barrier permeability and is involved in neural transmission and glial cell immune function and metabolism
Fig. 4
Fig. 4
CD73 expression on primary brain endothelial cells (EC). a Histogram depicting CD73 expression on primary brain endothelial cells isolated from naïve, WT, C57BL/6 mice after staining with a monoclonal antibody to CD73 and analyzed by FACS. b Expression of CD73 (green) on cultured primary human brain endothelial cells visualized by immunofluorescent microscopy. Cells were counterstained with F-actin (red). Scale bar is 50 μm
Fig. 5
Fig. 5
Expression of adenosine receptors (ARs) and adenosine-generating enzymes on brain endothelial cells. a A1 and A2A ARs expression green on primary human brain endothelial cells by immunofluorescence assay (IFA). Cells were counterstained with F-actin (red). b Relative mRNA expression level of ARs, CD39 and CD73 by quantitative PCR (q-PCR) in mouse primary brain endothelial cells. Scale bar is 50 μm
Fig. 6
Fig. 6
Adenosine increases the permeability of the blood brain barrier to 10 kDa FITC dextran. Concomitant administration of Adenosine and 10 kDa FITC-Dextran in C57BL/6 mice with exogenous adenosine induces significantly higher accumulation of FITC-Dextran into the brain than PBS control treatment group (n = 2, asterisk indicates p < 0.01)
Fig. 7
Fig. 7
A model: Adenosine modulation of blood brain barrier (BBB) permeability. Endothelial cells lining the brain vasculature express adenosine receptors (ARs) and CD39 and CD73. In the presence of cell stress/inflammation or tissue damage (a), ATP is released and is rapidly converted to ADP and AMP by CD39 (b) and AMP is converted to adenosine by CD73. c Adenosine binds to its receptor/s (A1 or A2A) on BBB endothelial cells (d), the activation of which induces reorganization of actin cytoskeleton in BBB endothelial cells, resulting in tight and adherens junction disassembly (e), increasing paracellular permeability
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