Functional role of adenosine receptor subtypes in the regulation of blood–brain barrier permeability: possible implications for the design of synthetic adenosine derivatives

• Published in: European journal of pharmaceutical sciences 2003-05, Vol.19 (1), p.13-22
• Main Authors: Schaddelee, Marloes P., Voorwinden, Heleen L., van Tilburg, Erica W., Pateman, Tony J., Ijzerman, Adriaan P., Danhof, Meindert, de Boer, Albertus G.
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Adenosine receptors; Animals; Astrocytes - metabolism; Biological and medical sciences; Biological Transport - physiology; Blood-Brain Barrier - physiology; Blood–brain barrier; Brain - blood supply; Capillaries - cytology; Cattle; Cell Membrane Permeability; Cells, Cultured; Coculture Techniques; Drug Design; Endothelium, Vascular - metabolism; Functionality; Humans; In vitro; Medical sciences; Models, Biological; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nucleoside Transport Proteins - metabolism; Nucleoside transporters; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, Purinergic P1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Species Specificity
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/S0928-0987(03)00034-4

The objective of this investigation was to determine the functional role of adenosine receptor subtypes in the regulation of blood–brain barrier (BBB) permeability. The presence of the equilibrative es and ei nucleoside transporters at the BBB was also determined. Studies were conducted in an experimental in vitro BBB model comprising bovine brain capillary endothelial cells (BCECs) and rat astrocytes (RAs). The presence of the receptors and transporters was investigated by a combination of RT-PCR and radioligand binding assays. Changes in paracellular permeability were investigated on basis of changes in trans-endothelial-electrical-resistance (TEER) and transport of paracellular markers. In BCECs the presence of A 2A and A 3 receptors and the es nucleoside transporter was demonstrated. The A 1 receptor was absent, while the presence of the A 2B receptor and the ei nucleoside transporter remained uncertain. In RAs the presence of all four receptor subtypes and the es and ei nucleoside transporters was demonstrated. Upon application of selective agonists no significant changes in TEER or the transport of the paracellular markers were observed. The functional role of adenosine receptor subtypes in regulating the paracellular permeability of the BBB is probably small. It is unlikely therefore that the BBB transport of synthetic adenosine analogues is modified by permeability changes. The es nucleoside transporter might play a role in the BBB transport of synthetic adenosine analogues.