Polarized effects of adenosine on blood-brain barrier integrity: Tightening from the luminal and opening from the abluminal side

Harazin, András and Hurtado-Alvarado, Gabriela and Barna, Lilla and de Oca, Arturo Contis-Montes and Ruiz-Manzano, Rocio and Laczi, Krisztián and Kincses, András and Porkoláb, Gergő and Chen, Gang and Gomez-Gonzalez, Beatriz and Deli, Mária Anna (2026) Polarized effects of adenosine on blood-brain barrier integrity: Tightening from the luminal and opening from the abluminal side. BRITISH JOURNAL OF PHARMACOLOGY, 183 (16). pp. 4761-4777. ISSN 0007-1188

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Abstract

Background and Purpose Adenosine as a signalling molecule modifies blood–brain barrier (BBB) tightness in pathological conditions. Our aim was to investigate the direct and polarized effects of adenosine on the BBB using co-culture and in vivo models. Experimental Approach The expression of adenosine receptors was measured by qRT-PCR. BBB models were prepared from primary rat brain endothelial cells, pericytes and glial cells and were treated with adenosine and A2A receptor antagonist SCH-58261 in the luminal and abluminal compartments. Barrier function in cultures was tested by impedance kinetics, electrical resistance and fluorescein permeability. Acute effects of intracardiac or intracerebroventricular adenosine were measured on the BBB permeability for fluorescein in the brain cortex and hippocampus of rats and mice. Key Results Adenosine receptors were present in BBB cells and brain endothelial cells expressed predominantly A2A receptors. Adenosine exerted a polarized effect on both in vitro and in vivo models; it tightened the paracellular barrier from the luminal side and increased fluorescein permeability from the abluminal or brain side. The abluminal, but not the luminal effect, was observed in sleep and in sleep deprivation. Based on the receptor profile, the results of co-culture experiments and the blocking effects of SCH-58261, the effect is mainly mediated luminally on brain endothelial, abluminally on brain endothelial and pericyte adenosine receptors. Conclusion and Implications Adenosine had a polarized circadian effect on BBB permeability, from the luminal side tightened the barrier in culture models and in vivo, whereas it opened the barrier from the abluminal side.

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