Dynamic Regulation of P-glycoprotein in Human Brain Capillaries

Considering its role as a major blood-brain barrier gatekeeper, the dynamic regulation of the efflux transporter P, glycoprotein is of considerable functional relevance. In particular, disease-associated alterations in transport function might affect Central nervous system drug efficacy. Thus, targeting regulatory signaling cascades might render a basis for novel therapeutic approaches. Using capillaries freshly prepared from patient tissue resected during epilepsy surgery, we demonstrate dynamic regulation of P-glycoprotein in human brain capillaries. Glutamate proved to up-regulate P-glycoprotein efflux transport in a significant manner via endothelial NMDA receptors. Both inhibition of :cyclooxygenase72 and antagonism at the,:glycine-binding site of the NMDA receptor prevented the glutamate mediated induction of P-glycoprotein transport function in human capillaries. In,conclusion, the data argue against species differences in the;signaling factors increasing endothelial P-glycoprotein :transport function in response to glutamate exposure. Targeting of cyclo-oxygenase-2 and of the NMDA receptor glycine-binding site was confirmed as an efficacious approach to control P-glycoprotein function. The findings might render, basis for translational development of add-on approaches to improve brain penetration and efficacy of drugs.