PURPOSE: To investigate the influence of astrocytes on P-glycoprotein (Pgp) expression and intracellular accumulation of Pgp substrates, separate from their net transcellular transport across the blood-brain barrier (BBB). METHODS: An in vitro BBB model was used, comprising of brain capillary endothelial cells (BCEC) monolayers or BCEC co-cultured with astrocytes. RESULTS: BCEC+astrocyte co-cultures seemed to express a higher level of Pgp compared to BCEC monolayers. Inhibition of Pgp results in an increased intracellular accumulation of Pgp substrates in both BCEC monolayers and BCEC+astrocyte co-cultures, and increased the sensitivity for vinblastine mediated disruption of the in vitro BBB (called the vinblastine exclusion assay). BCEC monolayers were more sensitive to vinblastine mediated disruption compared to BCEC+astrocyte co-cultures. In the latter, but not in BCEC monolayers, an inhibitable polar transport of Pgp substrates was only found from the brain to the blood side of the filter. CONCLUSIONS: Astrocytes increase the functional expression of Pgp in our in vitro BBB model. These results also illustrate that an important role for Pgp on the BBB is to protect the barrier against intracellular accumulation of cytotoxic BBB disrupting compounds.
PURPOSE: To investigate the influence of astrocytes on P-glycoprotein (Pgp) expression and intracellular accumulation of Pgp substrates, separate from their net transcellular transport across the blood-brain barrier (BBB). METHODS: An in vitro BBB model was used, comprising of brain capillary endothelial cells (BCEC) monolayers or BCEC co-cultured with astrocytes. RESULTS:BCEC+astrocyte co-cultures seemed to express a higher level of Pgp compared to BCEC monolayers. Inhibition of Pgp results in an increased intracellular accumulation of Pgp substrates in both BCEC monolayers and BCEC+astrocyte co-cultures, and increased the sensitivity for vinblastine mediated disruption of the in vitro BBB (called the vinblastine exclusion assay). BCEC monolayers were more sensitive to vinblastine mediated disruption compared to BCEC+astrocyte co-cultures. In the latter, but not in BCEC monolayers, an inhibitable polar transport of Pgp substrates was only found from the brain to the blood side of the filter. CONCLUSIONS: Astrocytes increase the functional expression of Pgp in our in vitro BBB model. These results also illustrate that an important role for Pgp on the BBB is to protect the barrier against intracellular accumulation of cytotoxic BBB disrupting compounds.
Authors: A M Yahanda; K M Alder; G A Fisher; N A Brophy; J Halsey; R I Hardy; M P Gosland; B L Lum; B I Sikic Journal: J Clin Oncol Date: 1992-10 Impact factor: 44.544
Authors: Hans C Helms; N Joan Abbott; Malgorzata Burek; Romeo Cecchelli; Pierre-Olivier Couraud; Maria A Deli; Carola Förster; Hans J Galla; Ignacio A Romero; Eric V Shusta; Matthew J Stebbins; Elodie Vandenhaute; Babette Weksler; Birger Brodin Journal: J Cereb Blood Flow Metab Date: 2016-02-11 Impact factor: 6.200
Authors: Inge van Rooy; Serpil Cakir-Tascioglu; Pierre-Olivier Couraud; Ignacio A Romero; Babette Weksler; Gert Storm; Wim E Hennink; Raymond M Schiffelers; Enrico Mastrobattista Journal: Pharm Res Date: 2010-02-17 Impact factor: 4.200