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Πέμπτη 12 Οκτωβρίου 2017

Adenosine A2A receptor agonist ameliorates EAE and correlates with Th1 cytokine-induced blood brain barrier dysfunction via suppression of MLCK signaling pathway

Abstract

Introduction

Multiple sclerosis (MS) disease activity is associated with blood-brain barrier (BBB) disruption, which is mediated by inflammatory cytokines released by CD4+ lymphocytes. To assess the effects of adenosine A2A receptors on BBB permeability in vitro and in vivo.

Methods

A2A receptor expression was detected by immunostaining in experimental autoimmune encephalomyelitis (EAE) C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG)35–55, and human MS brain. F-actin and the tight junction protein Claudin-5 were assessed in endothelial cells treated with an A2A receptor specific agonist (CGS-21680) after Th1 cytokine stimulation. EAE mice were divided into control and CGS-21680 (50 µg/kg, i.p., daily) groups. Disease scores were recorded daily to evaluate neurological impairment. The effects of A2A receptor on inflammation and demyelination were assessed after euthanasia by immunostaining or histology; BBB permeability was measured by sodium fluoride (Na-F) and FITC-dextran amounts.

Results

Endothelial A2A receptor was detected in demyelination areas of MS brain samples. In EAE lesions, A2A receptor was expressed in the endothelium in association with immune cell infiltration. Treatment with CGS-21680 counteracted the effects of Th1 cytokines on endothelial cells in vitro, preventing the reduction of tight junction protein expression and stress fiber formation. The effects of A2A receptor activation were correlated with MLCK phosphorylation signaling repression. In EAE, A2A receptor agonist decreased BBB permeability and inhibited EAE neurologic deficiency in mice.

Conclusions

A2A receptor activation at EAE onset helps reduce the effects of Th1 stimulation on BBB permeability, indicating that A2A receptor mediates BBB function in CNS demyelinated disease.

Thumbnail image of graphical abstract

We report on the effects of manipulating the A2A adenosine receptors on BBB permeability which could attenuated experimental autoimmune encephalomyelitis which is typical experimental model of MS. This is significant because increased permeability of the BBB associated with inflammation is significantly diminished by activation of the A2A receptors. The paper should be of interest to readers in the areas of multiple sclerosis.



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