Can inhibition of phosphodiesterase 6 mimic the oxidative stress phenotype in vivo found in mice with a loss-of-function phosphodiesterase 6 mutation?

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.