Treatment with A2A receptor antagonist KW6002 and caffeine intake regulate microglia reactivity and protect retina against transient ischemic damage

Raquel Boia,Maria H Madeira,Christa E Müller,Younis Baqi,António F Ambrósio,Inês D Aires,Rodrigo A Cunha,Ana C Rodrigues-Neves,Ana R Santiago,Eszter C Szabó,Pedro Tralhão,Ângelo R Tomé,Filipe Elvas

doi:10.1038/cddis.2017.451

Abstract

Transient retinal ischemia is a major complication of retinal degenerative diseases and contributes to visual impairment and blindness. Evidences indicate that microglia-mediated neuroinflammation has a key role in the neurodegenerative process, prompting the hypothesis that the control of microglia reactivity may afford neuroprotection to the retina against the damage induced by ischemia–reperfusion (I–R). The available therapeutic strategies for retinal degenerative diseases have limited potential, but the blockade of adenosine A2A receptor (A2AR) emerges as candidate strategy. Therefore, we evaluated the therapeutic potential of a selective A2AR antagonist (KW6002) against the damage elicited by I–R. The administration of KW6002 after I–R injury reduced microglia reactivity and inflammatory response and afforded protection to the retina. Moreover, we tested the ability of caffeine, an adenosine receptor antagonist, in mediating protection to the retina in the I–R injury model. We demonstrated that caffeine administration dually regulated microglia reactivity and cell death in the transient retinal ischemic model, depending on the reperfusion time. At 24 h of reperfusion, caffeine increased microglial reactivity, inflammatory response and cell death elicited by I–R. However, at 7 days of reperfusion, caffeine administration decreased microglia reactivity and reduced the levels of proinflammatory cytokines and cell death. Together, these results provide a novel evidence for the use of adenosine A2AR antagonists as potential therapy for retinal ischemic diseases and demonstrate the effect of caffeine on the regulation of microglia-mediated neuroinflammation in the transient ischemic model.

Highlights

Transient retinal ischemia refers to a pathological condition that involves loss of blood supply to the tissue, resulting in energy depletion, dysfunction, damage and death of neuronal cells.[1]
We demonstrated that A2A receptor (A2AR) antagonist prevents retinal ganglion cells (RGCs) death through the control of microglia-mediated neuroinflammation.[5,13]
We evaluated whether A2AR-knockout (KO) animals were less prone to neuroinflammation triggered by ischemic damage in the retina

Summary

Introduction

Transient retinal ischemia refers to a pathological condition that involves loss of blood supply to the tissue, resulting in energy depletion, dysfunction, damage and death of neuronal cells.[1]. Caffeine is the most widely consumed psychoactive drug and at nontoxic doses targets the adenosine receptors, mainly the inhibitory adenosine A1 receptor (A1R) and the facilitatory A2AR.[14] Caffeine has been demonstrated to afford robust neuroprotection under different neurotoxic situations in the brain, an effect that is mediated by the blockade of A2AR.[15,16,17,18,19] we found that caffeine attenuated the loss of retinal ganglion cells (RGCs) in animals with ocular hypertension.[20] Still, it remains unknown whether caffeine protects against retinal I–R injury as this is a pathophysiological process contributing to cellular damage in multiple ocular conditions

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