Abstract
Retinal hypoxia and oxidative stress are involved in several retinal degenerations including diabetic retinopathy, glaucoma, central retinal artery occlusion, or retinopathy of prematurity. The second messenger cyclic guanosine monophosphate (cGMP) has been reported to be protective for neuronal cells under several pathological conditions including ischemia/hypoxia. The purpose of this study was to evaluate whether the accumulation of cGMP through the pharmacological inhibition of phosphodiesterase (PDE) with Zaprinast prevented retinal degeneration induced by mild hypoxia in cultures of porcine retina. Exposure to mild hypoxia (5% O2) for 24h reduced cGMP content and induced retinal degeneration by caspase dependent and independent (PARP activation) mechanisms. Hypoxia also produced a redox imbalance reducing antioxidant response (superoxide dismutase and catalase activities) and increasing superoxide free radical release. Zaprinast reduced mild hypoxia-induced cell death through inhibition of caspase-3 or PARP activation depending on the cell layer. PDE inhibition also ameliorated the effects of mild hypoxia on antioxidant response and the release of superoxide radical in the photoreceptor layer. The use of a PKG inhibitor, KT5823, suggested that cGMP-PKG pathway is involved in cell survival and antioxidant response. The inhibition of PDE, therefore, could be useful for reducing retinal degeneration under hypoxic/ischemic conditions.
Highlights
Retinal cell death derived from ischemia occurs in several retinal diseases including central retinal artery occlusion, glaucoma, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and ischemic central retinal vein thrombosis [1,2,3,4,5]
Retinal hypoxia and oxidative stress have been implicated in the pathophysiology of several retinopathies such as age related macular degeneration (AMD), retinopathy of prematurity, central retinal vein occlusion (CRVO), diabetic retinopathy, glaucoma or branch retinal vein occlusion (BRVO) [4, 12, 45,46,47]
In the current study we assessed whether mild hypoxia (5% O2) induced retinal degeneration in an ex vivo porcine retina explant model
Summary
Retinal cell death derived from ischemia occurs in several retinal diseases including central retinal artery occlusion, glaucoma, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and ischemic central retinal vein thrombosis [1,2,3,4,5]. During retinal ischemia blood supply is reduced to an insufficient level leading to a lack of oxygen or hypoxia. This hypoxia can lead to serious consequences such as failure of energy balance causing ATP depletion, reactive oxygen species (ROS)-induced damage of cellular components, PLOS ONE | DOI:10.1371/journal.pone.0166717. Phosphodiesterase Inhibition and Retinal Hypoxia research-contract SNS Miguel Servet [CP09/118] from ISCIII This hypoxia can lead to serious consequences such as failure of energy balance causing ATP depletion, reactive oxygen species (ROS)-induced damage of cellular components, PLOS ONE | DOI:10.1371/journal.pone.0166717 November 18, 2016
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