Potential Regulation Mechanisms of P-gp in the Blood-Brain Barrier in Hypoxia

(E-pub Ahead of Print)

Author(s): Yidan Ding, Rong Wang*, Jianchun Zhang, Anpeng Zhao, Hui Lu, Wenbin Li, Chang Wang, Xuechun Yuan.

Journal Name: Current Pharmaceutical Design

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Abstract:

Blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances such as toxics and drugs between cerebral interstitial fluid and blood, keeping the relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is P-glycoprotein (P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-β (PKC-β)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However, the hypoxic signaling pathway of P-gp has never been studied in brain microvascular endothelial cells so far. According to the previous researches, hypoxia affects the expression and activity of the transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug delivery in CNS; If the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.

Keywords: P-gp, Blood-brain barrier (BBB), signaling pathway, hypoxia, drug, transcription factor

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(E-pub Ahead of Print)
DOI: 10.2174/1381612825666190610140153
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