Influence of gender on blood brain barrier permeability and adenosine receptor signaling

Abstract

The blood brain barrier (BBB) is a highly selective barrier that separates the circulating blood from the brain extracellular fluid, acting as a protective wall that allows for the passage of nutrients into the brain while blocking the entry of toxic factors. In addition, transporters expressed on brain endothelial cells, such as P‐glycoprotein (Pg‐p), selectively regulate the influx of key molecules necessary for proper brain function, thus imposing additional restrictions on permeability. Although protective, the BBB is a major hurdle for drug delivery to the central nervous system (CNS). We have shown that adenosine, a molecule produced by the enzyme CD73 in response to CNS injury, increases BBB permeability and allows the entry of macromolecules into the brain. Activation of adenosine receptor A2A with an FDA‐approved adenosine receptor agonist (Lexiscan) potently induced BBB permeability in mice and in primary human brain endothelial cell barriers. However, previous studies have shown that the kinetics of BBB breakdown may be different between males and females. Here, we investigate whether adenosine receptor‐mediated permeabilization of the BBB is deferentially regulated in male and female mice. We showed that endothelial cells from the healthy female mouse brain have significantly higher protein levels of Pg‐p compared to endothelial cells from healthy male mice. In vitro treatment of brain endothelial cells with Lexiscan induces greater intracellular accumulation of the P‐gp substrate Rhodamine 123 in brain endothelial cells from male mice compared to those from female mice. We also observed faster and longer‐lasting accumulation of Epirubicin, another Pg‐p substrate, in the brains of healthy male mice following I.V treatment with both Epirubicin and Lexiscan. Our studies could have an impact on how we look at treatment for many disorders of the CNS that affect the BBB and may reveal whether we need to revisit our approach regarding proper drug dosing regimens for the treatment of neurological diseases in males and females.