Reductions in Serum Vitamin A Arrest Accumulation of Toxic Retinal Fluorophores: A Potential Therapy for Treatment of Lipofuscin-Based Retinal Diseases

Radu, Roxana A.; Han, Yun; Bui, T. V.; Nusinowitz, Steven; Bok, Dean; Lichter, Jay B.; Widder, Ken; Travis, Gabriel H.; Mata, Nathan L.

doi:10.1167/iovs.05-0820

Cited by 208 publications

(180 citation statements)

References 41 publications

Supporting

Mentioning

169

Contrasting

Unclassified

Order By: Relevance

“…Because the photodegradative processes examined here could over time be responsible for cumulative damage to retina and Bruch's membrane, the present findings have implications with respect to development of therapeutics that address bisretinoid lipofuscin deposition in recessive Stargardt disease and AMD (55)(56)(57)(58)(59)(60) and justify efforts to protect the retina of STGD1 patients by reducing light exposure through the use of a black contact lens (61). Quantitative Fundus Autofluorescence.…”

Section: Discussionmentioning

confidence: 86%

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration

show abstract

Section: Discussionmentioning

confidence: 86%

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

show abstract

“…Several approaches under investigation involve limiting bisretinoid formation (42)(43)(44). A number of reports, including from the Age-Related Eye Disease Study, have also demonstrated a role for antioxidant intake in protecting against AMD progression (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration

Yanase

Feng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

130

125

View full text Add to dashboard Cite

Fluorescent bisretinoids, such as A2E and all-trans-retinal dimer, form as a by-product of vitamin A cycling in retina and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin pigments. These pigments are implicated in pathological mechanisms involved in several vision-threatening diseases including age-related macular degeneration. Efforts to understand damaging events initiated by these bisretinoids have revealed that photoexcitation of A2E by wavelengths in the visible spectrum leads to singlet oxygen production and photooxidation of A2E. Here we have employed liquid chromatography coupled to electrospray ionization mass spectrometry together with tandem mass spectrometry (MS/MS), to demonstrate that A2E also undergoes photooxidation-induced degradation and we have elucidated the structures of some of the aldehyde-bearing cleavage products. Studies in which A2E was incubated with a singlet oxygen generator yielded results consistent with a mechanism involving bisretinoid photocleavage at sites of singlet molecular oxygen addition. We provide evidence that one of the products released by A2E photodegradation is methylglyoxal, a low molecular weight reactive dicarbonyl with the capacity to form advanced glycation end products. Methylglyoxal is already known to be generated by carbohydrate and lipid oxidation; this is the first report of its production via bisretinoid photocleavage. It is significant that AGE-modified proteins are detected in deposits (drusen) that accumulate below RPE cells in vivo; drusen have been linked to age-related macular degeneration pathogenesis. Whereas various processes play a role in drusen formation, these findings are indicative of a contribution from lipofuscin photooxidation in RPE.advanced glycation end products | lipofuscin | photofragmentation | photooxidation | retinal pigment epithelial cells F luorescent bisretinoid pigments are amassed as lipofuscin in retinal pigment epithelial (RPE) cells in association with aging although individuals vary with respect to the extent of accumulation (1). The excessive deposition of these compounds in RPE cells is also considered to lead to retinal degeneration in early onset blinding disorders associated with mutations in the genes encoding ABCA4 (ATP-binding cassette subfamily A member 4) (2, 3), ELOVL4 (4), and BEST-1 (5). Moreover, the deposition of these pigments likely also contributes to the etiology of agerelated macular degeneration (AMD) (6, 7). Whereas these bisretinoids constitute a complex mixture, all appear to originate from reactions of all-trans-retinal and some have been identified, including A2E (Fig. 1) and its isomers (8); A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE) and A2-dihydropyridine-ethanolamine (A2-DHP-E) (9); and all-trans-retinal dimer, all-trans-retinal dimer-phosphatidylethanolamine (all-transretinal dimer-PE), and all-trans-retinal dimer-ethanolamine (alltrans-retinal dimer-E) (10, 11). Structural features common to all of these pigments are the alternating single and double carbon...

show abstract

“…The excessive formation of these compounds in Stargardt macular degeneration, is considered to be the cause of a loss of RPE cells in recessive Stargardt disease, a blinding macular disorder of juvenile onset and probably also contributes to the etiology of age-related macular degeneration (AMD), a common cause of blindness in elderly people (Delori et al, 2001;Holz et al, 2001;Radu et al, 2005;Schmitz-Valckenberg et al, 2004;Scholl et al, 2004). Photochemical reactions initiated by excitation from the blue region of the spectrum may contribute to the adverse effects of lipofuscin accumulation.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms involved in A2E oxidation

Kim

Jockusch

Itagaki

et al. 2008

Experimental Eye Research

View full text Add to dashboard Cite

A2E is one of the bis-retinoid pyridinium compounds that accumulate as lipofuscin pigments in retinal pigment epithelial (RPE) cells in association with aging and in some inherited forms of retinal degeneration. Here we observed that 430 nm irradiation of A2E in the presence of the spin trap DMPO, led to the appearance of a superoxide dismutase-inhibitable electron paramagnetic resonance (EPR) spectrum characteristic of DMPO-OH; this finding was indicative of hydroxyl radical (OH) formation following initial spin trapping of superoxide anion by DMPO. We also observed an increase in dihydroethidium (HEt) fluorescence and luminol-based chemiluminescence that on the basis of inhibition by superoxide dismutase, was indicative of superoxide anion generation when A2E was irradiated at 430 nm in cell-free systems. Nevertheless, while A2E was readily oxidized in the presence of a singlet oxygen generator, superoxide anion did not serve to oxidize A2E. Specifically, by HPLC quantitation and FAB-mass spectroscopy, there was no evidence of A2E oxidation when A2E was incubated with a superoxide anion generator (xanthine/xanthine oxidase) in a variety of solvents (100% PBS, 30% DMSO in PBS, 100% MeOH and CHCl 3 ) or in the presence of detergent. On the other hand, however, peroxy-A2E, an oxidized form of A2E with an endoperoxide moiety on the short-arm of the molecule, readily underwent further oxygen addition when incubated with xanthine/xanthine oxidase. Superoxide anion may be generated by irradiation of A2E but is not involved in the early events that oxidize A2E. Superoxide can contribute to the further oxidation of already-oxidized A2E.

show abstract

Reductions in Serum Vitamin A Arrest Accumulation of Toxic Retinal Fluorophores: A Potential Therapy for Treatment of Lipofuscin-Based Retinal Diseases

Abstract: These findings demonstrate the vitamin A-dependent nature of A2E biosynthesis and validate a novel therapeutic approach with potential to halt the accumulation of lipofuscin fluorophores in the eye.

Cited by 208 publications

References 41 publications

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration

Mechanisms involved in A2E oxidation

Contact Info

Product

Resources

About