July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Can inhibition of phosphodiesterase 6 mimic the oxidative stress phenotype in vivo found in mice with a loss-of-function phosphodiesterase 6 mutation?
Author Affiliations & Notes
  • Collin Richards
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Hailey Olds
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Joydip Joy
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Tilman Rosales
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Robert H Podolsky
    Beaumont Research Institute, Royal Oak, Michigan, United States
  • Karen M Lins-Childers
    Beaumont Research Institute, Royal Oak, Michigan, United States
  • Robin Roberts
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Bruce A Berkowitz
    Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Footnotes
    Commercial Relationships   Collin Richards, None; Hailey Olds, None; Joydip Joy, None; Tilman Rosales, None; Robert Podolsky, None; Karen Lins-Childers, None; Robin Roberts, None; Bruce Berkowitz, None
  • Footnotes
    Support  Fight for Sight Summer Student Fellowship, National Eye Institute (RO1 EY026584, RO1 AG058171 to BAB), NEI Core Grant P30 EY04068, and an unrestricted grant from Research to Prevent Blindness (Kresge Eye Institute).
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 32. doi:https://doi.org/
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      Collin Richards, Hailey Olds, Joydip Joy, Tilman Rosales, Robert H Podolsky, Karen M Lins-Childers, Robin Roberts, Bruce A Berkowitz; Can inhibition of phosphodiesterase 6 mimic the oxidative stress phenotype in vivo found in mice with a loss-of-function phosphodiesterase 6 mutation?. Invest. Ophthalmol. Vis. Sci. 2019;60(9):32. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : rd10 mice with a loss-of-function phosphodiesterase 6 (PDE6) mutation show outer retinal oxidative stress (PMC5868999, PMC6057918). Here we test the hypothesis that pharmacological PDE6 inhibition alone is sufficient to reproduce this pathophenotype in vivo.

Methods : Dark or light adapted C57BL/6 mice were treated with a high, non-clinical dose of sildenafil (29 mg/kg, IP), a PDE5 inhibitor that also strongly inhibits rod PDE6 (PMID: 25239397, PMID: 15224133). Excessive free radical production in vivo was evaluated at 1 hour post sildenafil treatment based on hemiretina and layer-specific 1/T1 values with and without the anti-oxidants methylene blue (MB and α-lipoic acid (ALA)) [i.e., QUEnch-assiSTed MRI (QUEST MRI)]. Retinal layer spacing and thickness in vivo also were measured (optical coherence tomography, MRI).

Results : In darkness, evidence for oxidative stress was found in inferior retina at 0-48% depth (i.e., all inner retina layers and outer plexiform layer) at 400 to 1000 mm from the optic nerve head (ONH) and at 0-8% depth (i.e., retinal ganglion cell layer) at 1000 – 2000 mm from the ONH; no evidence was found for oxidative stress in the superior retina. In light, evidence for oxidative stress was found in superior retina at 80 – 88% depth (i.e., outer segment layer) only at 1000 – 2000 mm from the ONH in superior retina. Retinal thicknesses were unremarkable in all groups.

Conclusions : These findings raise the possibility that rod PDE6 inhibition per se contributes to the etiology of outer retina oxidative stress in rd10 mice in a light-dependent fashion.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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