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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis

Authors: Volodymyr Gerzanich, Tapas K. Makar, Poornachander Reddy Guda, Min Seong Kwon, Jesse A. Stokum, Seung Kyoon Woo, Svetlana Ivanova, Alexander Ivanov, Rupal I. Mehta, Alexandra Brooke Morris, Joseph Bryan, Christopher T. Bever, J. Marc Simard

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), inflammation is perpetuated by both infiltrating leukocytes and astrocytes. Recent work implicated SUR1-TRPM4 channels, expressed mostly by astrocytes, in murine EAE. We tested the hypothesis that pharmacological inhibition of SUR1 during the chronic phase of EAE would be beneficial.

Methods

EAE was induced in mice using myelin oligodendrocyte glycoprotein (MOG) 35–55. Glibenclamide (10 μg/day) was administered beginning 12 or 24 days later. The effects of treatment were determined by clinical scoring and tissue examination. Drug within EAE lesions was identified using bodipy-glibenclamide. The role of SUR1-TRPM4 in primary astrocytes was characterized using patch clamp and qPCR. Demyelinating lesions from MS patients were studied by immunolabeling and immunoFRET.

Results

Administering glibenclamide beginning 24 days after MOG35–55 immunization, well after clinical symptoms had plateaued, improved clinical scores, reduced myelin loss, inflammation (CD45, CD20, CD3, p65), and reactive astrocytosis, improved macrophage phenotype (CD163), and decreased expression of tumor necrosis factor (TNF), B-cell activating factor (BAFF), chemokine (C-C motif) ligand 2 (CCL2) and nitric oxide synthase 2 (NOS2) in lumbar spinal cord white matter. Glibenclamide accumulated within EAE lesions, and had no effect on leukocyte sequestration. In primary astrocyte cultures, activation by TNF plus IFNγ induced de novo expression of SUR1-TRPM4 channels and upregulated Tnf, Baff, Ccl2, and Nos2 mRNA, with glibenclamide blockade of SUR1-TRPM4 reducing these mRNA increases. In demyelinating lesions from MS patients, astrocytes co-expressed SUR1-TRPM4 and BAFF, CCL2, and NOS2.

Conclusions

SUR1-TRPM4 may be a druggable target for disease modification in MS.
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Metadata
Title
Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis
Authors
Volodymyr Gerzanich
Tapas K. Makar
Poornachander Reddy Guda
Min Seong Kwon
Jesse A. Stokum
Seung Kyoon Woo
Svetlana Ivanova
Alexander Ivanov
Rupal I. Mehta
Alexandra Brooke Morris
Joseph Bryan
Christopher T. Bever
J. Marc Simard
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0953-z

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