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Megan Stiles, Nawajes A Mandal, Madeline Budda, Gary White, Roman Wolf, Richard Steven Brush, Robert Floyd, Robert E Anderson; Topically Administered PBN and Methyl-PBN inhibits the visual cycle and slows rhodopsin regeneration in mice and baboon eyes.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5411.
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A2E and related toxic molecules are part of lipofuscin found in the retinal pigment epithelial (RPE) cells in AMD eyes. A novel therapeutic approach for AMD involves slowing down the visual cycle, which could reduce the amount of A2E in the RPE. This can be accomplished by inhibiting RPE65, which produces 11-cis-retinal from all-trans-retinyl esters. We discovered that phenyl-N-tert-butylnitrone (PBN), a spin trap agent, protects the retina from light-induced retinal degeneration (LIRD). PBN injected in rats slowed the rate of rhodopsin regeneration and recovery consistent with a slowing of the visual cycle and protected the retina from LIRD. In this study, we tested 1) whether topically administered PBN and certain PBN-derivatives can slow the rate of the visual cycle in mouse eyes and 2) the effects of PBN and Methyl-PBN (Me-PBN) in baboon eyes.
An eye drop formulation was used for topical application of PBN and its derivatives. To measure the effect of PBN on rhodopsin regeneration, light-adapted mice were given drops of PBN solution or vehicle followed by dark adaptation for 1 hour to recover bleachable rhodopsin. Eyes were harvested and rhodopsin levels measured spectrophotometrically. We developed various PBN derivatives, which were also tested under the same conditions as PBN. PBN and one of its derivatives, Me-PBN were topically applied to light-adapted baboon eyes followed by 1 hour dark adaptation to recover bleachable rhodopsin. Pieces of retina were harvested and used for rhodopsin measurement. The levels of PBN and Me-PBN in RPE-choroid tissue were measured by mass spectrometry.
One hour dark adaptation resulted in 75-80% recovery of bleachable rhodopsin in control/vehicle mice. Eye drops containing 10% PBN inhibited (50-70%) the regeneration of bleachable rhodopsin. Among PBN derivatives, 5% Me-PBN was most effective, inhibiting the regeneration of bleachable rhodopsin by 70%. PBN and Me-PBN were then tested in anesthetized baboon eyes. PBN inhibited the visual cycle by 40%, whereas Me-PBN inhibited the cycle by 70% in baboons.
We conclude that topically applied PBN and its derivative Me-PBN can reach the target tissue and slow the rate of rhodopsin regeneration and therefore the visual cycle in both mouse and baboon eyes. PBN and its derivatives can potentially be developed as preventative treatment in human AMD.
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