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Rong Zhou, Cun Wang, Bin Lin, Yanyan Wang, Jiangfan Chen, Xiaoling Liu; Chronic treatment of caffeine and adenosine A2A receptor antagonist KW6002 selectively protects against oxygen-induced retinal neovascular damage in mice. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):214.
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Clinical trial with caffeine treatment for sleep apnea in premature infants suggests that ROP is reduced in two-year follow-up observation. Furthermore, we recently demonstrated genetic inactivation of Adenosine A2A receptor (A2AR), the main target of caffeine action in the brain, protected retinal pathological neovascularization (NV). The aim of this study was to evaluate the therapeutic effects of caffeine, as well as A2AR antagonists, on retinal NV in an oxygen-induced retinopathy (OIR) model.
Seven-day old C57BL/6J mice kept with the nursing mice were exposed to 75% oxygen for 5 days to induce vaso-obliteration. At P12, the mice returned to room air to induce retinal neovascularizaion, which was maximal at P17. The nursing mothers were given caffeine solution (0.1, 0.3, and 1.0g/L) or water, starting from the first day after delivery until P7, or P12 or P17. Immunostaining, HE staining, and RT-PCR were used to assess retinal nonvascular area and neovascular responses.
For the effect of caffeine on vaso-obliteration, we found caffeine treatment at the concentration of 0.1 g/L (P<0.05) and 1.0 g/L (P<0.001) from P0-P17 reduced avascular areas by 53.78 % and 31.28 %, respectively. For effect on vaso-proliferation, chronic caffeine treatment from P0-P17 reduced NV area by 44.13%, compared to the OIR mice treated with water. Quantitative neovascular nuclei counting also showed a dramatic inhibition of OIR pathologic changes from (86.99±4.52) to (42.88±3.17)(P<0.001) (N=45). Interestingly, caffeine treatment from P0 to P7, which was equivalently effective as from P0-P17, significantly diminished nonvascular area (10.98±1.64% vs. 17.58±1.41%, P<0.05 ). Furthermore, we also found that compared to the vehicle-treated mice, repeated treatment of KW6002 at P7-P14 reduced avascular area as well as neovascularization at P17 (p<0.0001). Lastly, chronic treatment with caffeine or KW6002 did not affect normal retinal angiogenesis during postnatal development as revealed by flat mount and retinal sections.
Our finding provides the direct evidence that chronic caffeine pretreatment selectively attenuated oxygen-induced pathologic angiogenesis without affecting normal postnatal development. Thus, caffeine and A2A receptor antagonists may represent important therapeutic strategy for treating retinopathy of prematurity.
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