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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit

Authors: William A. Banks, Alicia M. Gray, Michelle A. Erickson, Therese S. Salameh, Mamatha Damodarasamy, Nader Sheibani, James S. Meabon, Emily E. Wing, Yoichi Morofuji, David G. Cook, May J. Reed

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Disruption of the blood-brain barrier (BBB) occurs in many diseases and is often mediated by inflammatory and neuroimmune mechanisms. Inflammation is well established as a cause of BBB disruption, but many mechanistic questions remain.

Methods

We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in mice. BBB disruption was measured using 14C-sucrose and radioactively labeled albumin. Brain cytokine responses were measured using multiplex technology and dependence on cyclooxygenase (COX) and oxidative stress determined by treatments with indomethacin and N-acetylcysteine. Astrocyte and microglia/macrophage responses were measured using brain immunohistochemistry. In vitro studies used Transwell cultures of primary brain endothelial cells co- or tri-cultured with astrocytes and pericytes to measure effects of LPS on transendothelial electrical resistance (TEER), cellular distribution of tight junction proteins, and permeability to 14C-sucrose and radioactive albumin.

Results

In comparison to LPS-induced weight loss, the BBB was relatively resistant to LPS-induced disruption. Disruption occurred only with the highest dose of LPS and was most evident in the frontal cortex, thalamus, pons-medulla, and cerebellum with no disruption in the hypothalamus. The in vitro and in vivo patterns of LPS-induced disruption as measured with 14C-sucrose, radioactive albumin, and TEER suggested involvement of both paracellular and transcytotic pathways. Disruption as measured with albumin and 14C-sucrose, but not TEER, was blocked by indomethacin. N-acetylcysteine did not affect disruption. In vivo, the measures of neuroinflammation induced by LPS were mainly not reversed by indomethacin. In vitro, the effects on LPS and indomethacin were not altered when brain endothelial cells (BECs) were cultured with astrocytes or pericytes.

Conclusions

The BBB is relatively resistant to LPS-induced disruption with some brain regions more vulnerable than others. LPS-induced disruption appears is to be dependent on COX but not on oxidative stress. Based on in vivo and in vitro measures of neuroinflammation, it appears that astrocytes, microglia/macrophages, and pericytes play little role in the LPS-mediated disruption of the BBB.
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Metadata
Title
Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit
Authors
William A. Banks
Alicia M. Gray
Michelle A. Erickson
Therese S. Salameh
Mamatha Damodarasamy
Nader Sheibani
James S. Meabon
Emily E. Wing
Yoichi Morofuji
David G. Cook
May J. Reed
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0434-1

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