Dynamic regulation of P-glycoprotein in human brain capillaries

• Verfasst von: Avemary, Janine Verena [VerfasserIn]
• Verfasst von: Salvamoser, Josephine D. [VerfasserIn]
• Verfasst von: Peraud, Aurelia [VerfasserIn]
• Verfasst von: Rémi, Jan [VerfasserIn]
• Verfasst von: Noachtar, Soheyl [VerfasserIn]
• Verfasst von: Fricker, Gert [VerfasserIn]
• Verfasst von: Potschka, Heidrun [VerfasserIn]
• Titel: Dynamic regulation of P-glycoprotein in human brain capillaries
• Verf.angabe: Janine Avemary, Josephine D. Salvamoser, Aurelia Peraud, Jan Rémi, Soheyl Noachtar, Gert Fricker, and Heidrun Potschka
• E-Jahr: 2013
• Jahr: July 18, 2013
• Fussnoten: Gesehen am 23.10.2020
• Titel Quelle: Enthalten in: Molecular pharmaceutics
• Ort Quelle: Washington, DC : American Chemical Society, 2004
• Jahr Quelle: 2013
• Band/Heft Quelle: 10(2013), 9, Seite 3333-3341$9
• ISSN Quelle: 1543-8392
• DOI: doi:10.1021/mp4001102
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1736490974

Abstract

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 cyclooxygenase-2 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 cyclooxygenase-2 and of the NMDA receptor glycine-binding site was confirmed as an efficacious approach to control P-glycoprotein function. The findings might render a basis for translational development of add-on approaches to improve brain penetration and efficacy of drugs.