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Jianhai Du, Andrei O. Chertov, Austin Rountree, Martin Sadilek, Ian R. Sweet, James B. Hurley; Relationships Between Pde6 Inhibition, Energy Metabolism And Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1601.
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To understand the relationships between energy metabolism and retinal degeneration, we identified metabolic changes induced by phosphodiesterase 6 (PDE6) inhibition and ways to rescue the photoreceptor cell death by restoring the dysfunctional metabolism.
Mouse retina was isolated and cultured in Krebs-Ringer bicarbonate buffer with glucose. Phosphodiesterase activity was inhibited by zaprinast. cGMP was measured by EIA kit. Photoreceptor cell death was evaluated by propidium iodide uptake in the photoreceptor layer of NRL-GFP mice by confocal microscopy. Citric acid cycle intermediates and amino acids were measured by GC-MS. ATP was determined by luciferase assay and the oxygen consumption was measured by a perfusion apparatus.
There were little cell death (<10 cells/field) in normal retinas within 4 h incubation but PDE inhibition induced significant photoreceptor cell death at 2 h (24 ± 4/field) and 4 h (4336 ± 354/field) in light-adapted retinas. At 2h, PDE inhibition caused increases of pyruvate and aspartate and a dramatic decrease of glutamate in both light and dark-adapted mice. Furthermore, PDE inhibition repressed the mitochondrial oxygen consumption. However, the ATP concentration slightly increased upon PDE inhibition. At 4 h, the glutamate remained extremely low and the mitochondrial intermediates also decreased with PDE inhibition but the ATP concentration still was comparable to the control. Supplementation with glutamine (10 mM) brought glutamate and mitochondrial intermediates to normal levels, improved mitochondrial oxygen consumption and partially rescued the photoreceptor cell death caused by PDE inhibition.
Photoreceptor cell death induced by PDE inhibition may be caused by depletion of glutamate and exhaustion of mitochondrial metabolites. Metabolite supplementation may be a successful approach for treating certain types of retinal degeneration.
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