Abstract
Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal circulation. However, the detailed mechanisms of this process remain elusive. Here we demonstrate that neovascular AMD with subretinal hemorrhage accompanies a significant increase in extracellular ATP, and that extracellular ATP initiates neurodegenerative processes through specific ligation of Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7; P2X7 receptor). Increased extracellular ATP levels were found in the vitreous samples of AMD patients with subretinal hemorrhage compared to control vitreous samples. Extravascular blood induced a massive release of ATP and photoreceptor cell apoptosis in co-culture with primary retinal cells. Photoreceptor cell apoptosis accompanied mitochondrial apoptotic pathways, namely activation of caspase-9 and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, as well as TUNEL-detectable DNA fragmentation. These hallmarks of photoreceptor cell apoptosis were prevented by brilliant blue G (BBG), a selective P2RX7 antagonist, which is an approved adjuvant in ocular surgery. Finally, in a mouse model of subretinal hemorrhage, photoreceptor cells degenerated through BBG-inhibitable apoptosis, suggesting that ligation of P2RX7 by extracellular ATP may accelerate photoreceptor cell apoptosis in AMD with subretinal hemorrhage. Our results indicate a novel mechanism that could involve neuronal cell death not only in AMD but also in hemorrhagic disorders in the CNS and encourage the potential application of BBG as a neuroprotective therapy.
Highlights
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly in the developed world [1]
A few TUNEL+ cells were found after this injection in contrast to the case with subretinal hemorrhage (Figure 1, B and C), suggesting that a massive hemorrhage could severely reduce the integrity of photoreceptors, if it were tightly packed into the subretinal space
Age-related Macular Degeneration To examine the potential role of extracellular ATP in subretinal hemorrhage, we investigated the intraocular concentrations of ATP by using vitreous samples collected during vitreoretinal surgery from patients with MH, ERM, or age-related macular degeneration (AMD) with vitreous hemorrhage (VH)
Summary
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly in the developed world [1]. In the neovascular form of this disorder, severe visual loss commonly occurs as a result of the invasion of abnormal blood vessels from the choroidal circulation, namely choroidal neovascularization (CNV), which induces irreversible damage to the overlying retina [3]. CNV could be induced by focally increased inflammatory and proangiogenic factors and/or by a decrease in anti-angiogenic factors. Various clinical as well as experimental studies have shown that vascular endothelial growth factor (VEGF), a proangiogenic glycoprotein, could be the most important factor for development of CNV [4]. Pharmacological inhibition of VEGF has offered the first opportunity to improve visual outcomes in patients diagnosed with this disorder [5]. Intraocular injections of an anti-VEGF antibody, such as ranibizumab or bevacizumab, have improved visual outcomes in several clinical trials [6]
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