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HMGB1 contributes to the expression of P-Glycoprotein in mouse epileptic brain through toll-like receptor 4 and receptor for advanced glycation end products

Chen, Y and Huang, XJ and Yu, N and Xie, Y and Zhang, K and Wen, F and Liu, H and Di, Q (2015) HMGB1 contributes to the expression of P-Glycoprotein in mouse epileptic brain through toll-like receptor 4 and receptor for advanced glycation end products. PLoS ONE, 10 (10).

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Abstract

© 2015 Chen et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1) in the seizure-induced P-glycoprotein (P-gp) overexpression and the underlying mechanism. Kainic acid (KA)-induced mouse seizure model was used for in vivo experiments. Male C57BL/6 mice were divided into four groups: normal saline control (NS) group, KA-induced epileptic seizure (EP) group, and EP group pretreated with HMGB1 (EP +HMGB1 group) or BoxA (HMGB1 antagonist, EP+BoxA group). Compared to the NS group, increased levels of HMGB1 and P-gp in the brain were observed in the EP group. Injection of HMGB1 before the induction of KA further increased the expression of P-gp while pre-treatment with BoxA abolished this up-regulation. Next, the regulatory role of HMGB1 and its potential involved signal pathways were investigated in mouse microvascular endothelial bEnd.3 cells in vitro. Cells were treated with HMGB1, HMGB1 plus lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) [toll-like receptor 4 (TLR4) antagonist], HMGB1 plus FPS-ZM1 [receptor for advanced glycation end products (RAGE) inhibitor], HMGB1 plus SN50 [nuclear factor-kappa B (NF-êB) inhibitor], or vehicle. Treatment with HMGB1 increased the expression levels of P-gp, TLR4, RAGE and the activation of NF-êB in bEnd.3 cells. These effects were inhibited by the pre-treatment with either LPS-RS or FPS-ZM1, and were abolished by the pre-treatment of SN50 or a combination treatment of both LPS-RS and FPS-ZM1. Luciferase reporter assays showed that exogenous expression of NF-êB p65 increased the promoter activity of multidrug resistance 1a (P-gp-encoding gene) in endothelial cells. These data indicate that HMGB1 contributes to the overexpression of P-gp in mouse epileptic brain tissues via activation of TLR4/RAGE receptors and the downstream transcription factor NF-κB in brain microvascular endothelial cells.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chen, Y
Huang, XJ
Yu, N
Xie, Y
Zhang, K
Wen, F
Liu, Hhal14@pitt.eduHAL14
Di, Q
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorAhmad, MuzamilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 20 October 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0140918
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurology
Refereed: Yes
Date Deposited: 23 Aug 2016 14:43
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/28372

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