Blockade of Adenosine A(2A) Receptor Protects Photoreceptors after Retinal Detachment by Inhibiting Inflammation and Oxidative Stress

PURPOSE: Adenosine A(2A) receptor (A(2A)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(2A)R antagonist ZM241385 would prevent photoreceptor apoptosis by inhibiting retinal inflammation and oxidative stress after RD. METHODS: The A(2A)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(2A)R expression, microglia proliferation and reactivity, glial fibrillary acidic protein (GFAP) accumulation, IL-1β expression, and reactive oxygen species (ROS) production were evaluated with immunofluorescence. Photoreceptor TUNEL was analyzed. RESULTS: A(2A)R expression obviously increased and accumulated in microglia and Müller cells in the retinas after RD. The A(2A)R antagonist ZM241385 effectively inhibited retinal microglia proliferation and reactivity, decreased GFAP upregulation and proinflammatory cytokine IL-1β expression of Müller cells, and suppressed ROS overproduction, resulting in attenuation of photoreceptor apoptosis after RD. CONCLUSIONS: The A(2A)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(2A)R blockade may be an important therapeutic strategy to protect photoreceptors in RD and other CNS diseases that share a common etiology.