Adenosine Receptor Signaling Modulates Permeability of the Blood–Brain Barrier

Abstract

The blood-brain barrier (BBB) is comprised of specialized endothelial cells that form the capillary microvasculature of the central nervous system (CNS) and is essential for brain function. It also poses the greatest impediment in the treatment of many CNS diseases because it commonly blocks entry of therapeutic compounds. Here we report that adenosine receptor (AR) signaling modulates BBB permeability in vivo. A1 and A2A AR activation facilitated the entry of i.v.-administered macromolecules, including large dextrans and antibodies to β-amyloid, into murine brains. Additionally, treatment with an FDA-approved selective A2A agonist, Lexiscan, also increased BBB permeability in murine models. These changes in BBB permeability are dose-dependent and temporally discrete. Transgenic mice lacking A1 or A2A ARs showed diminished dextran entry into the brain after AR agonism. Following treatment with a broad spectrum AR agonist, i.v.-administered anti-β-amyloid antibody was observed to enter the CNS and bind β-amyloid plaques in a transgenic mouse model of Alzheimer’s disease (AD). Selective AR activation resulted in cellular changes in vitro including decreased transendothelial electrical resistance, increased actinomyosin stress fiber formation, and alterations in tight junction molecules. These results suggest that AR signaling can be used to modulate BBB permeability in vivo to facilitate the entry of potentially therapeutic compounds into the CNS. AR signaling at brain endothelial cells represents a novel endogenous mechanism of modulating BBB permeability. We anticipate these results will aid in drug design, drug delivery and treatment options for neurological diseases such as AD, Parkinson’s disease, multiple sclerosis and cancers of the CNS.

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

“…A variety of transporters and receptors are highly expressed on brain endothelial cells that selectively restrict or allow the entry of substances, some of which are necessary for normal brain function, such as glucose and amino acids, while others are expelled (14,55). Our previous studies showed that activation of the A2A AR increases BBB permeability to entry of large molecules that is mediated by increased paracellular permeability, induced RhoA activity, and rearrangement of the actin-cytoskeleton in brain endothelial cells (44,59). However, 6, A-C).…”

“…Previously, we have shown that ARmediated signaling increases the permeability of the BBB to large molecules in vivo and in vitro (44,59). In this study, to test the hypothesis that AR signaling regulates P-gp function, we used in vitro BBB models to determine whether AR signaling can indeed inhibit the expression and function of P-gp.…”

“…Many drugs developed for treatment of brain disorders are largely classified as P-gp substrates; thus, significant efforts are placed on developing methods to bypass the hindrance posed by P-gp (27,42,43). Recent studies from our lab showed adenosine receptor (AR) signaling regulates the permeability of the BBB (44,45).…”

“…The drug-binding pocket of P-gp is nonspecific, and this allows for a broad spectrum of drugs as substrates (24)(25)(26). Recent studies sug-2-{4-[(methylamino)carbonyl]-1H-pyrazol-1-yl}adenosine (Lexiscan), increased accumulation of drugs into the brain in a time-and dose-dependent manner (45). BBB opening under AR signaling was reversible.…”

Adenosine A2A receptor agonist ameliorates EAE and correlates with Th1 cytokine‐induced blood brain barrier dysfunction via suppression of MLCK signaling pathway

“…Endothelial cells express several or all four known adenosine receptors, including A1, A2a, A2b, and A3 6. Adenosine limits the secretion of the cytokines IL‐6 and IL‐8 by acting on A2A receptors 7. Adenosine also prevents the increase of vascular permeability, and thus promotes endothelial barrier integrity 7.…”