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

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

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 10 , 2019


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Abstract:

The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances, such as toxins 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 Pglycoprotein (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, it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain microvascular endothelial cells. According to previous research, 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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VOLUME: 25
ISSUE: 10
Year: 2019
Published on: 05 August, 2019
Page: [1041 - 1051]
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DOI: 10.2174/1381612825666190610140153
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