Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Abstract

PURPOSE. Diabetes appears to induce a visual cycle defect because rod dysfunction is correctable with systemic treatment of the visual cycle chromophore 11-cis-retinaldehyde. However, later studies have found no evidence for visual cycle impairment. Here, we further examined whether photoreceptor dysfunction is corrected with 11-cis-retinaldehyde. Because antioxidants correct photoreceptor dysfunction in diabetes, the hypothesis that exogenous visual chromophores have antioxidant activity in the retina of diabetic mice in vivo was tested.METHODS. Rod function in 2-month-old diabetic mice was evaluated using transretinal electrophysiology in excised retinas and apparent diffusion coefficient (ADC) MRI to measure light-evoked expansion of subretinal space (SRS) in vivo. Optokinetic tracking was used to evaluate cone-based visual performance. Retinal production of superoxide free radicals, generated mostly in rod cells, was biochemically measured with lucigenin. Diabetic mice were systemically treated with a single injection of either 11-cis-retinaldehyde, 9-cisretinaldehyde (a chromophore surrogate), or all-trans-retinaldehyde (the photoisomerization product of 11-cis-retinaldehyde).RESULTS. Consistent with previous reports, diabetes significantly reduced (1) dark-adapted rod photo responses (transretinal recording) by~18%, (2) rod-dominated light-stimulated SRS expansion (ADC MRI) by~21%, and (3) cone-dominated contrast sensitivity (using optokinetic tracking [OKT]) by~30%. Both 11-cis-retinaldehyde and 9-cis-retinaldehyde largely corrected these metrics of photoreceptor dysfunction. Higher-than-normal retinal superoxide production in diabetes by~55% was also significantly corrected following treatment with 11-cis-retinaldehyde, 9-cis-retinaldehyde, or all-trans-retinaldehyde.CONCLUSIONS. Collectively, data suggest that retinaldehydes improve photoreceptor dysfunction in diabetic mice, independent of the visual cycle, via an antioxidant mechanism.

Rod phototransduction and light signal transmission during type 2 diabetes

“…This is consistent with lack of photoreceptor loss (35) and absence of reports of reduced scotopic ERGs in patients with diabetes. Since other studies have shown attenuated photoreceptor function in ex vivo transretinal recordings from STZ mice (36), our findings may not be universal and restricted to the db/db mouse as a model of type 2 diabetes. It is also possible that compromised rod photoreceptor function in the STZ mouse model is due to known neurotoxic effects of STZ (37) rather than a consequence of diabetes.…”

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

“…Glaucoma [137] Retinoids Systemically administration reduces retinal OS and correct rod dysfunction. DR [138] Finally, other treatments for retinal dystrophies are based on promoting cytoprotective pathways. As aforementioned, RP is a mendelian rare disease caused by mutation in many genes but increasing evidence in patients and animal models suggests that oxidative stress and inflammation contribute to its pathogenesis irrespective of the causative gene.…”

Do photoreceptor cells cause the development of retinal vascular disease?

“…Potential approaches include the use of light (photobiomodulation) or agents that affect photoreceptors by direct or indirect means, including retinylamine, and agonists and antagonists of G-protein coupled receptors [28] (which are known to be prevalent in photoreceptors). Administration of other retinaldehydes has corrected diabetes-induced photoreceptor dysfunction (including subnormal dark-adapted rod photoresponses, rod-dominated light-stimulated expansion of the subretinal space, and cone-dominated contrast sensitivity), potentially via an antioxidant mechanism [68]. The extent to which the visual cycle contribute to the retinopathy, and the possibility that light-initiated phototransduction or subsequent changes in photoreceptor ion channel activities also might contribute to the molecular processes leading to DR merit further investigation.…”