Abstract
Purpose Adenosine A2A receptor (A2AR) 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 A2AR antagonist ZM241385 would prevent photoreceptor apoptosis by inhibiting retinal inflammation and oxidative stress after RD. Methods The A2AR 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. A2AR 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 A2AR expression obviously increased and accumulated in microglia and Müller cells in the retinas after RD. The A2AR 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 A2AR 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 A2AR blockade may be an important therapeutic strategy to protect photoreceptors in RD and other CNS diseases that share a common etiology.
Highlights
Photoreceptor apoptosis because of physical separation of the photoreceptors from the retinal pigment epithelium (RPE) results in visual loss in a number of retinal diseases, including macular degeneration [1], retinopathy of prematurity [2], diabetic retinopathy [3], and retinal detachment (RD) [4, 5]
Reactive microglia cells are prevalent in the detached retina where they play a principal role in RD-induced photoreceptor apoptosis [10]
To investigate whether the A2A receptor (A2AR) blockade contributes to inhibiting reactive gliosis and inflammatory responses after RD, we evaluated the role of A2AR in the RD-induced glial fibrillary acidic protein (GFAP) and IL-1β expression
Summary
Photoreceptor apoptosis because of physical separation of the photoreceptors from the retinal pigment epithelium (RPE) results in visual loss in a number of retinal diseases, including macular degeneration [1], retinopathy of prematurity [2], diabetic retinopathy [3], and retinal detachment (RD) [4, 5]. Photoreceptors are extremely vulnerable and undergo apoptosis in various types of RD including rhegmatogenous, tractional, and exudative. Surgical treatment is routinely carried out to reattach the retina, visual acuity is not always restored because of RD-induced photoreceptor apoptosis [4, 5]. The development of neuroprotective agents for photoreceptors is essential to provide visual stability for RD patients undergoing surgical treatment. In RD, multiple pathways are known to be involved in the RD-induced photoreceptor apoptosis, including the caspase pathway, autophagy, inflammation and gliosis, and reactive oxygen species (ROS) [6,7,8,9]. Reactive microglia cells are prevalent in the detached retina where they play a principal role in RD-induced photoreceptor apoptosis [10].
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