Table 3.

Examples of A2A receptor agonists with a proven effect on altering the permeability of the BBB.

Adenosine 2A Agonist	Mechanism of Action	Clinical Application	Research Object/Model	Effect on BBB Permeability	References
Regadenoson (CVT-3146/ Lexiscan)	Selective adenosine 2A receptor agonist	FDA approval for pharmacologic cardiac stress testing (detection of coronary artery disease)	In vitro: primary human brain endothelial cell monolayers	Increase in BBB permeability for 10 kDa FITC-dextran mainly from 5 to 30 min after administration	[62]
			In vivo: murine models	Increased permeability of the BBB to 10 kDa FITC-dextran (maximal concentration after 30 min)	[62]
			In vivo: -murine models -rat models	Increased CNS dextran entry over time (maximum after 30 min) in both mice and rats	[83]
			Clinical study—patients with glioblastoma	No significant difference in TMZ concentrations in CNS before and after administration of Lexiscan	[63]
			In vivo: -murine models -rat models	Significantly increased concentration of voltage sensitive dye (VSD) in rat brain tissue and increased residence time of the VDS fluorescence signal in mouse brains.	[87]
			In vivo: rat models	Significantly higher brain temozolomide concentrations at 120 min after regadenoson and TMZ administration	[48]
NECA (5‘-N-Ethylcarboxamidoadenosine)	Broad-spectrum adenosine receptor agonist	Not yet approved by the FDA	In vitro: -primary human brain endothelial cell monolayers	Increase in BBB permeability for 10 kDa FITC-dextran mainly from 60 to 90 min after administration	[62]
			In vivo: -murine models -rat models	Increased entry of 10 kDa and 70 kDa dextrans into WT mouse brain 3 h after intravenous administration	[83]
CGS 21680	Selective adenosine 2A receptor agonist	Not yet approved by the FDA	In vivo: -murine models	Increased entry of 10 kDa FITC-dextran into WT brain tissue 3 h after intravenous administration	[83]