The specialized endothelial cells of the blood-brain barrier (BBB) protect the brain from toxic substances, while allowing oxygen and other nutrients to pass through. The selectivity of the BBB also prevents delivery of therapeutic agents to the brain that could benefit patients with neurological diseases. In this episode, Margaret Bynoe reveals that activation of the A2A adenosine receptor (A2A AR) with the FDA-approved agonist Lexiscan reversibly reduced expression of the drug efflux transporters P-glycoprotein and BCRP1. Moreover, in mouse models, Lexisacn treatment resulted in a greater accumulation of chemotherapeutic drugs in the brain. The results of this study indicate that targeting A2A AR should be further explored for improving drug-delivery to the brain.
The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer’s disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.
Do-Geun Kim, Margaret S. Bynoe