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Regulation of Multidrug Resistance P‐Glycoprotein in the Developing Blood–Brain Barrier: Interplay between Glucocorticoids and Cytokines
Author(s) -
Iqbal M.,
Baello S.,
Javam M.,
Audette M. C.,
Gibb W.,
Matthews S. G.
Publication year - 2016
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12360
Subject(s) - p glycoprotein , glucocorticoid , dexamethasone , in vivo , medicine , proinflammatory cytokine , blood–brain barrier , endocrinology , cytokine , glucocorticoid receptor , tumor necrosis factor alpha , biology , interleukin 6 , interleukin , immunology , inflammation , central nervous system , multiple drug resistance , drug resistance , microbiology and biotechnology
P‐glycoprotein (P‐gp) encoded by Abcb1 provides protection to the developing brain from xenobiotics. P‐gp in brain endothelial cells ( BEC s) derived from the developing brain microvasculature is up‐regulated by glucocorticoids and inhibited by pro‐inflammatory cytokines in vitro . However, little is known about how prenatal maternal glucocorticoid treatment can affect Abcb1 /P‐gp function and subsequent cytokine regulation in foetal BEC s. We hypothesised that glucocorticoid exposure increases Abcb1 /P‐gp in the foetal brain microvasculature and enhances the sensitivity of Abcb1 /P‐gp in BEC s to the inhibitory effects of cytokines. BEC s isolated from dexamethasone‐ or vehicle‐exposed foetal guinea pigs were cultured and treated with interleukin‐1β, interleukin‐6 or tumour necrosis factor‐α, and Abcb1 /P‐gp expression and function were assessed. Prenatal dexamethasone exposure significantly increased Abcb1 /P‐gp expression/activity and cytokine receptor levels in BEC s of the foetal brain microvasculature. Foetal dexamethasone exposure in vivo also increased the subsequent responsiveness of BEC s to pro‐inflammatory cytokines in vitro . In conclusion, maternal treatment with synthetic glucocorticoids appears to prematurely mature P‐gp mediated drug resistance at the foetal BBB in vivo and profoundly impact the subsequent responsiveness of P‐gp to pro‐inflammatory cytokines in the foetal BEC . The significance of these findings to foetal brain protection against xenobiotics and other P‐gp substrates in vivo requires further elaboration. However, the results of the present study may have implications for human pregnancy and foetal brain protection, particularly in cases of preterm birth combined with infection.