Expression and function of ABC-transporters at the blood brain barrier are essential for the barrier function. Both are subject of complex signaling cascades and nuclear receptors (orphan receptors) play a pivotal role in these processes. They respond to internal and external stimuli including metabolites, xenobiotics, pollutants and drugs. To date 48 nuclear receptors have been identified in humans. Exposing brain capillaries to ligands of the pregnane X receptor, one of these nuclear receptors, increases p-glycoprotein expression and Pgp–specific transport of substrates into capillary lumens. In vivo dosing of rats with nuclear receptor ligands results in increased p-gp expression and function in brain capillaries. A second nuclear receptor at the BBB is AhR, Aryl hydrocarbon receptor, which responds to a large variety of environmental toxins, including DDT or TCDD. In rat capillaries, incubation with AhR-substrates results in increased expression of Pgp, Mrp2 and Bcrp, which can be suppressed by AhR antagonists. These results show that ABC transporters at the BBB are target genes of nuclear receptors, which act as cellular xenosensors. Ligand activation of the receptors results in an upregulation of transporters and thus, for substrates that are toxicants or potentially toxic metabolic wastes, increased transporter expression should be protective for the brain. Function of ABC transporters is also regulated by trace elements such as Zinc. Exposure of brain capillaries to Zn²+ results in a significant functional upregulation of Pgp, Mrp2 and Bcrp at the BBB.
To enhance drug transport across the BBB, ABC transporters can be bypassed by use of surface modified colloidal carriers, such as liposomes or polymeric nanoparticles. E.g., administration of biodegradable polybutylcyanoacrylate nanoparticles results in significant drug accumulation of otherwise poorly permeable drugs in the brain.