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

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.

Blockade of microglial adenosine A2A receptor suppresses elevated pressure‐induced inflammation, oxidative stress, and cell death in retinal cells

“…Modeling ocular hypertension in vitro increased the expression of TSPO and MHC‐II in retinal neural cells, consistent with a response of microglia to elevated pressure. Also, A 2A R antagonist prevented this increase, suggesting that microglial A 2A R controls neuroinflammation, as has been suggested previously (Boia et al, ; Madeira et al, ).…”

“…The blockade of A 2A R confers neuroprotection in several models of neurodegeneration, including in the retina (Boia et al, ; Boia et al, ; Cunha, ; Gomes, Kaster, Tome, Agostinho, & Cunha, ; Gyoneva et al, ; Liu et al, ; Madeira, Boia, et al, ; Madeira, Elvas, et al, ). One of the mechanisms that may explain the protective properties of A 2A R antagonists is the control of microglia‐mediated neuroinflammation (Cunha, ; Gomes et al, ).…”

“…Adenosine is a neuromodulator in the central nervous system acting through the activation of four receptors, A 1 , A 2A , A 2B , and A 3 . We demonstrated that the blockade of adenosine A 2A receptor (A 2A R) confers neuroprotection to the retina in glaucoma models through the control of microglia responsiveness (Boia et al, ; Boia, Ambrósio, & Santiago, ; Madeira et al, ; Madeira, Elvas, et al, ; Santiago et al, ). However, the specific role of microglial cells was not addressed, as well as the impact of A 2A R blockade in microglial cells in the context of glaucoma.…”

A2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

“…The use of nonselective and selective A 2A R antagonists, such as caffeine and SCH 58261, respectively, is considered as a potential therapeutic strategy for several neuropathological diseases (Boia et al, ; Laurent et al, 2014). In line with these studies, we suggest that this neuroprotective effect observed might be associated to a direct effect on astrocytic transcriptome by particularly downregulating the pro‐inflammatory gene, Il1ß, as well as decreasing Vim expression.…”

“…The different types of astrocytic reactivation, Panreactive, A1 and A2 specific were classified in Zamanian et al (2012). A1-specific reactivation is highly associated with neurodegenerative diseases, such as AD [Color figure can be viewed at wileyonlinelibrary.com] suggested that A 2A Rs expressed by microglia, the main resident inflammatory brain cell, play a critical role in the control of neuroinflammation (Rebola et al, 2011;Boia et al, 2017). Some findings suggest that microglia A 2A Rs might also be dysregulated in the pathological context of AD (Orr et al, 2009;Angulo et al, 2003).…”