【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/6 mice for three days at a dose (3mg/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.
【中文摘要】
目的：旨在研究腺苷A2A受體（A2AR）拮抗劑ZM241385對視網膜脫離（RD）小鼠光感受器細胞凋亡的調控作用。
方法：C57BL/6小鼠腹腔注射A2AR拮抗劑ZM241385（3mg/kg），自建立RD模型前2小時首次幹預，每天一次，連續三天。運用免疫螢光染色等方法檢測小鼠視網膜A2AR表達，小膠質細胞增殖和活性，神經膠質纖維酸性蛋白（GFAP）聚集，促炎性細胞因子IL-1β表達和活性氧（ROS）含量變化。通過TUNEL檢測視網膜光感受器細胞凋亡情況。
結果：在RD小鼠視網膜中A2AR表達顯著增加，並且主要聚集於小膠質細胞和Müller細胞表面。A2AR拮抗劑ZM241385幹預RD小鼠，可以顯著抑制視網膜小膠質細胞增殖和活性，降低Müller細胞GFAP和IL-1β表達，並抑制ROS的過度產生，從而有效減少RD後光感受器細胞凋亡的發生。
結論：A2AR拮抗劑ZM241385可以通過抑制神經炎症和氧化應激有效改善RD小鼠視網膜中光感受器細胞凋亡。