Superoxidation of Bisretinoids

Washington, Ilyas; Jockusch, Steffen; Itagaki, Yasuhiro; Turro, Nicholas J.; Nakanishi, Koji

doi:10.1002/ange.200501346

Cited by 8 publications

(9 citation statements)

References 22 publications

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“…Because of conjugated double bonds in its hydrophobic arms, A2E exhibits a yellow-orange fluorescence with an emission peak at ∼630 nm (λ max ) (14)(15)(16). Several studies indicate that A2E's λ max changes with the polarity of the medium (17)(18)(19).…”

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“…The absorption spectrum of A2E exhibits two absorbance maxima, at 340 and 440 nm, that correspond to the conjugated double bonds in the short and long arms of the molecule, respectively (14). In aqueous solution, A2E undergoes slow spontaneous oxidation manifested by progressive reduction of its absorbance peaks; upon exposure to blue light (∼430 nm) the oxidative destruction of A2E is much faster (22,23).…”

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Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

Nociari

Lehmann

Bay

et al. 2014

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

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Accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there are no approved treatments for these diseases; hence, agents that efficiently remove LBs from RPE would be valuable therapeutic candidates. Here, we show that beta cyclodextrins (β-CDs) bind LBs and protect them against oxidation. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of LBs within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from Abca4-Rdh8 double knock-out (DKO) mice, respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of DKO animals. Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs.aging | retinopathy | lipofuscinosis | residual bodies T he retinal pigment epithelium (RPE), strategically situated between the neural retina and the choroid blood vessels, is essential for photoreceptor (PR) function. It recycles vitamin A, which is required for the visual cycle and clears debris generated by the circadian shedding of PR outer segments (1, 2). Each RPE cell phagocytoses and digests the material produced by 30-50 overlying PRs, which shed 10% of their mass daily. The intense and continual phagocytic activity of RPE cells results in the progressive accumulation of indigestible products or "lipofuscin" in their lysosomal compartment (3, 4). Unlike lipofuscins found in other body tissues, which are composed mainly of protein, RPE lipofuscin consists predominantly of lipid-bisretinoids and only 2% protein (5). Lipofuscin bisretinoids (LBs) are vitamin A-derived side products of the visual cycle. Light converts 11-cis-retinal (11CR), the visual pigment chromophore, into all-trans-retinal (ATR), which is immediately flipped by the ATP-binding cassette transporter 4 (Abca4) transporter from the lumen of the outer segment discs to the cytoplasm, where it is reduced to inert all-trans-retinol by retinol dehydrogenase 8 (Rdh8), in mice (6, 7). Small fractions of 11CR and ATR are converted into N-retinylidine-N-ethanolamine (A2E) and other less abundant bisretinoids, which once accumulated in the lysosomes of RPE cells are refractory to all known lysosomal hydrolases (8, 9). The concept that LB accumulation causes retinal degeneration is supported by in vitro and in vivo data that show that excessive LBs are toxic for cultured RPE cells (10,11), that photoreceptors overlying A2E-laden RPE are more prone to degeneration (12) and that excessive accumulation of LBs in Stargardt's disease precedes macular degeneration (13). Mice carrying null mutations in Abca4 and Rdh8 develop blin...

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confidence: 99%

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confidence: 99%

Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

Nociari

Lehmann

Bay

et al. 2014

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

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“…A2‐E is a singlet oxygen sensitizer, and blue light irradiation in the presence of oxygen for 10 minutes forms a highly apoptotic A2‐E nonaoxirane ( 45 ) 72 . Oxidation products of bisretinoid are proposed to cause cell damage and death 73 . Nakanishi and coworkers showed that photodegradation of A2‐E in vitro and in RPE cells could be prevented by the addition of bilberry or the antioxidant anthocyanins contained therein 74 .…”

Section: Resultsmentioning

confidence: 99%

The enduring legacy of Koji Nakanishi's research on bioorganic chemistry and natural products. Part 1: Isolation, structure determination and mode of action

2020

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In this brief review on Koji Nakanishi's remarkable career in natural products chemistry, we have highlighted a number of his accomplishments that illustrate the broad diversity of his interests. These include the isolation, structure determination, and biological mechanism of action of many natural products including the triterpenoid pristimerin; the diterpenoid ginkgolides; insect and crustacean molting hormones; phytoalexins; the toxic red tide principle brevetoxin; the vanadium tunicate pigments; philanthotoxin from killer wasps; antisickling agents; mitomycin DNA adducts; insect antifeedants; a mitotic hormone, the small molecule fish attractants from the sea anemone; new isolation and purification technologies; molecular chemistry of vision; age‐related macular degeneration; and the development of the exciton circular dichroism (CD) chirality method for microscale determination of absolute configuration of natural products and chirality of other chiral molecules and supramolecular assembly.

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“…Compounds 15,98,101,103, and 107 led to the formation of bisperoxides. Growing experimental data has been accumulated for singlet oxygen reactions, which give rise to spiro compounds [82,83,[127][128][129][130], or yield bis-or polyperoxides, or polyepoxides [42,58,[114][115][116][117][118][119][120]131].…”

Section: Discussionmentioning

confidence: 99%

Singlet Oxygen as a Reagent in Organic Synthesis

Zamadar

Greer

2009

Handbook of Synthetic Photochemistry

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Superoxidation of Bisretinoids

Abstract: Eng und persönlich: Eng zusammenstehende Retinoidpolyene, wie sie auf dem rechten Sessel abgebildet sind, reagieren leicht mit Sauerstoff (rot) zu polyoxygenierten Verbindungen. Getrennte Polyene dagegen, wie sie auf dem linken Sofa zu sehen sind, werden nur eingeschränkt oxidiert.

Cited by 8 publications

References 22 publications

Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

The enduring legacy of Koji Nakanishi's research on bioorganic chemistry and natural products. Part 1: Isolation, structure determination and mode of action

Singlet Oxygen as a Reagent in Organic Synthesis

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