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Open Access 01-12-2015 | Research

Adenosine A_2AR blockade prevents neuroinflammation-induced death of retinal ganglion cells caused by elevated pressure

Authors: Maria H. Madeira, Filipe Elvas, Raquel Boia, Francisco Q. Gonçalves, Rodrigo A. Cunha, António Francisco Ambrósio, Ana Raquel Santiago

Published in: Journal of Neuroinflammation | Issue 1/2015

Abstract

Background

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a degenerative disease characterized by the loss of retinal ganglion cells (RGCs). There is clinical and experimental evidence that neuroinflammation is involved in the pathogenesis of glaucoma. Since the blockade of adenosine A_2A receptor (A_2AR) confers robust neuroprotection and controls microglia reactivity in the brain, we now investigated the ability of A_2AR blockade to control the reactivity of microglia and neuroinflammation as well as RGC loss in retinal organotypic cultures exposed to elevated hydrostatic pressure (EHP) or lipopolysaccharide (LPS).

Methods

Retinal organotypic cultures were either incubated with LPS (3 μg/mL), to elicit a pro-inflammatory response, or exposed to EHP (+70 mmHg), to mimic increased IOP, for 4 or 24 h, in the presence or absence of the A_2AR antagonist SCH 58261 (50 nM). A_2AR expression, microglial reactivity and neuroinflammatory response were evaluated by immunohistochemistry, quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). RGC loss was assessed by immunohistochemistry. In order to investigate the contribution of pro-inflammatory mediators to RGC loss, the organotypic retinal cultures were incubated with rabbit anti-tumour necrosis factor (TNF) (2 μg/mL) and goat anti-interleukin-1β (IL-1β) (1 μg/mL) antibodies.

Results

We report that the A_2AR antagonist (SCH 58261) prevented microglia reactivity, increase in pro-inflammatory mediators as well as RGC loss upon exposure to either LPS or EHP. Additionally, neutralization of TNF and IL-1β prevented RGC loss induced by LPS or EHP.

Conclusions

This work demonstrates that A_2AR blockade confers neuroprotection to RGCs by controlling microglia-mediated retinal neuroinflammation and prompts the hypothesis that A_2AR antagonists may be a novel therapeutic option to manage glaucomatous disorders.

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Title: Adenosine A2AR blockade prevents neuroinflammation-induced death of retinal ganglion cells caused by elevated pressure
Authors: Maria H. Madeira
Filipe Elvas
Raquel Boia
Francisco Q. Gonçalves
Rodrigo A. Cunha
António Francisco Ambrósio
Ana Raquel Santiago
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/s12974-015-0333-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Adenosine A_2AR blockade prevents neuroinflammation-induced death of retinal ganglion cells caused by elevated pressure

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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