Sildenafil-evoked photoreceptor oxidative stress in vivo is unrelated to impaired visual performance in mice

Abstract

Purpose The phosphodiesterase inhibitor sildenafil is a promising treatment for neurodegenerative disease, but it can cause oxidative stress in photoreceptors ex vivo and degrade visual performance in humans. Here, we test the hypotheses that in wildtype mice sildenafil causes i) wide-spread photoreceptor oxidative stress in vivo that is linked with ii) impaired vision. Methods In dark or light-adapted C57BL/6 mice ± sildenafil treatment, the presence of oxidative stress was evaluated in retina laminae in vivo by QUEnch-assiSTed (QUEST) magnetic resonance imaging, in the subretinal space in vivo by QUEST optical coherence tomography, and in freshly excised retina by a dichlorofluorescein assay. Visual performance indices were also evaluated by QUEST optokinetic tracking. Results In light-adapted mice, 1 hr post-sildenafil administration, oxidative stress was most evident in the superior peripheral outer retina on both in vivo and ex vivo examinations; little evidence was noted for central retina oxidative stress in vivo and ex vivo. In dark-adapted mice 1 hr after sildenafil, no evidence for outer retina oxidative stress was found in vivo. Evidence for sildenafil-induced central retina rod cGMP accumulation was suggested as a panretinally thinner, dark-like subretinal space thickness in light-adapted mice at 1 hr but not 5 hr post-sildenafil. Cone-based visual performance was impaired by 5 hr post-sildenafil and not corrected with anti-oxidants; vision was normal at 1 hr and 24 hr post-sildenafil. Conclusions The sildenafil-induced spatiotemporal pattern of oxidative stress in photoreceptors dominated by rods was unrelated to impairment of cone-based visual performance in wildtype mice.

Functional regulation of an outer retina hyporeflective band on optical coherence tomography images

“…The ELM-RPE thickness signal cascade outlined above is further supported by recent evidence. For example, reduced ELM-RPE thickness can be produced in light adapted C57BL6J mice by increasing mitochondria activity with a low dose of protonophore (i.e., uncoupler) or increasing circulating current with a phosphodiesterase 6 inhibitor 29 , 30 . In addition, a relatively smaller light–dark ELM-RPE thickness is found in wildtype 129S6/ev mice vs. C57BL/6J mice.…”

Retinal Toxicity Induced by Chemical Agents

“…In 5% of mice, sildenafil provoked RGC loss and damage of optic nerve after 21 days of the treatment. In an in vivo approach to evaluate the effect of sildenafil in the mouse retina, QUEnch-assiSTed (QUEST) magnetic resonance imaging (MRI) was used in subretinal space using QUEST optical coherence tomography (OCT), while QUEST optokinetic tracking (OKT) was used for cone-based vision [ 107 ]. QuestMRI showed an increase in oxidative stress in a group treated with sildenafil when compared to a group exposed to sildenafil plus antioxidants.…”

“…QuestMRI showed an increase in oxidative stress in a group treated with sildenafil when compared to a group exposed to sildenafil plus antioxidants. This effect was only detected in the peripheral superior retina [ 107 ]. Levels of ROS evaluated by DCF staining in freshly isolated retinal sections were higher all over the retina treated with sildenafil compared to saline, with more prominent labeling in the superior retina.…”

Transducin-Deficient Rod Photoreceptors Evaluated With Optical Coherence Tomography and Oxygen Consumption Rate Energy Biomarkers

“…Cone-based visual performance was tested by optokinetic tracking, which is also sensitive to outer retina dysfunction. 56 – 58 Although not studied herein, we note that retinas without rod transducin 1 α-subunit ( Gnat1 − / − ) exhibit oxidative stress, a condition that can modify pH and has been shown to induce ELM-RPE thinning in light-adapted mice. 31 , 59 , 60 In this study, we compared the three OCT biomarkers in Gnat1 rd17 mice given saline solution or antioxidants (i.e., QUEnch-assiSTed [QUEST] OCT).…”