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, target...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
July 18, 2013
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| In: |
Molecular pharmaceutics
Year: 2013, Volume: 10, Issue: 9, Pages: 3333-3341$9 |
| ISSN: | 1543-8392 |
| DOI: | 10.1021/mp4001102 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/mp4001102
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| Author Notes: | Janine Avemary, Josephine D. Salvamoser, Aurelia Peraud, Jan Rémi, Soheyl Noachtar, Gert Fricker, and Heidrun Potschka |
| Summary: | 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. |
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| Item Description: | Gesehen am 23.10.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1543-8392 |
| DOI: | 10.1021/mp4001102 |