Blockade of Adenosine A_2A Receptor Protects Photoreceptors after Retinal Detachment by Inhibiting Inflammation and Oxidative Stress

Abstract

<jats:p><jats:italic>Purpose</jats:italic>. Adenosine A<jats:sub>2A</jats:sub> receptor (A<jats:sub>2A</jats:sub>R) signaling is neuroprotective in some retinal damage models, but its role in neuronal survival during retinal detachment (RD) is unclear. We tested the hypothesis that A<jats:sub>2A</jats:sub>R antagonist ZM241385 would prevent photoreceptor apoptosis by inhibiting retinal inflammation and oxidative stress after RD. <jats:italic>Methods</jats:italic>. The A<jats:sub>2A</jats:sub>R antagonist ZM241385 was delivered daily to C57BL/6J mice for three days at a dose (3 mg/kg, i.p.) starting 2 hours prior to creating RD. A<jats:sub>2A</jats:sub>R expression, microglia proliferation and reactivity, glial fibrillary acidic protein (GFAP) accumulation, IL-1<jats:italic>β</jats:italic> expression, and reactive oxygen species (ROS) production were evaluated with immunofluorescence. Photoreceptor TUNEL was analyzed. <jats:italic>Results</jats:italic>. A<jats:sub>2A</jats:sub>R expression obviously increased and accumulated in microglia and Müller cells in the retinas after RD. The A<jats:sub>2A</jats:sub>R antagonist ZM241385 effectively inhibited retinal microglia proliferation and reactivity, decreased GFAP upregulation and proinflammatory cytokine IL-1<jats:italic>β</jats:italic> expression of Müller cells, and suppressed ROS overproduction, resulting in attenuation of photoreceptor apoptosis after RD. <jats:italic>Conclusions</jats:italic>. The A<jats:sub>2A</jats:sub>R antagonist ZM241385 is an effective suppressor of microglia proliferation and reactivity, gliosis, neuroinflammation, oxidative stress, and photoreceptor apoptosis in a mouse model of RD. This suggests that A<jats:sub>2A</jats:sub>R blockade may be an important therapeutic strategy to protect photoreceptors in RD and other CNS diseases that share a common etiology.</jats:p>

Regulations of Retinal Inflammation: Focusing on Müller Glia

“…Another type of adenosine receptor, Adenosine A 2A receptor (A 2A R), is also expressed by the MG. The inhibition of A 2A R decreases GFAP upregulation and IL-1β expression of MG, and suppresses ROS overproduction, resulting in attenuation of photoreceptor apoptosis after RD ( Gao et al, 2020 ).…”

Caffeine reduces oxidative stress to protect against hyperoxia-induced lung injury via the adenosine A2A receptor/cAMP/PKA/Src/ERK1/2/p38MAPK pathway

“…Indeed, previous research has indicated that A2AR is strongly associated with OS. The A2AR antagonist ZM241385 was an effective suppressor of microglial proliferation and reactivity, OS and photoreceptor apoptosis in a mouse model of retinal detachment [ 46 ].…”

Lipid Peroxidation in Subretinal Fluid: Some Light on the Prognosis Factors

“…The suggestion made by others [ 7 ] of using antioxidants to improve better visual recovery choices after RRD are of interest. Gao et al [ 35 ] demonstrated that blocking oxidative stress in experimental retinal detachment improved the apoptosis of photoreceptors. This may be an interesting future avenue of research to attempt to prevent the apoptosis of photoreceptors and, therefore, to improve the vision of patients with retinal detachment.…”