title: Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice.
abstract: OBJECTIVE
  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-cis-retinaldehyde (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.
authors.affiliation: Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Berkowitz
authors.affiliation: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.affiliation: Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
authors.forename: David
authors.initials: D
authors.lastname: Bissig
authors.affiliation: Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
authors.forename: Priya
authors.initials: P
authors.lastname: Patel
authors.affiliation: Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
authors.forename: Ankit
authors.initials: A
authors.lastname: Bhatia
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States.
authors.forename: Vladimir J
authors.initials: VJ
authors.lastname: Kefalov
authors.affiliation: Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Roberts
mesh_terms: D000818:Animals; D003623:Dark Adaptation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects*; D012172:Retinaldehyde / Q000494:pharmacology*
chemical_list: D012172:Retinaldehyde