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Leonide Saad, Dan Zhang, Ilyas Washington; Dark Adaptation Delays and Retinaldehyde Dimerization Products. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5407.
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© ARVO (1962-2015); The Authors (2016-present)
To elucidate the role of retinaldehyde dimerization products (RDP) on age-associated declines of dark adaptation.
Slowed dark adaptation occurs almost universally during the course of aging. However, the molecular mechanisms responsible for such delays are unknown. RDP are small molecule byproducts of the vitamin A cycle and are implicated in the pathogenesis of several retinal diseases. We used UPLC to quantify the amount of vitamin A and RDP in human eyes. To evaluate the effects of RDP on dark adaptation, we used a mouse model that displays increased ocular RDP, and modulated RDP in the animals by administering C20D3-vitamin A (ALK-001), a vitamin A with reduced dimerization propensity. Ocular RDP was also modulated in a wild-type rodent by intravitreal delivery of RDP. Dark adaptation was assessed by measuring the recovery of electroretinograms and rhodopsin regeneration kinetics following a controlled bleach. We used 2-tailed t-tests for statistical analyses.
RDPs accumulate with age in the human retina while total vitamin A remains stable: at approximately 70 years of age, the amount of RDP can surpass ocular vitamin A (~20,000 pmols per retina, N=18). In mouse models of accelerated RDP formation, ALK-001 retarded the age-related accumulation of RDP by over 80% (N=10, p<0.01) and reduced fundus autofluorescence (FAF) by about 70% (Fig. a).Mice that received ALK-001 had over 2-fold faster b-wave recovery than mice in the vitamin A group (N=10, p<0.01). Wild-type rodents intraocularly treated with a bolus of RDP soon displayed a 30% slowing of b-wave recovery, despite otherwise normal retinal electrophysiology and morphology. The observed delays in dark adaptation could be explained by RDP-induced delays in rhodopsin regeneration.
The age-related accumulation of RDP is sufficient alone to cause age-related declines in dark adaption. Data further show that progressive declines in dark adaptation are tractable to pharmacological intervention and reveal RDP as a therapeutic target. Finally, ALK-001 holds promise as a non-invasive, early preventive therapeutic to mitigate ubiquitous declines in visual performance.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
FAF (Fig. a) and b-wave amplitude (Fig b.) of mice reared on vitamin A or C20D3-vitamin A.
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