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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 14; pp. E1402 - E1408
• Main Authors: Nociari, Marcelo M, Lehmann, Guillermo L, Perez Bay, Andres E, Radu, Roxana A, Jiang, Zhichun, Goicochea, Shelby, Schreiner, Ryan, Warren, J David, Shan, Jufang, Adam de Beaumais, Ségolène, Ménand, Mickaël, Sollogoub, Matthieu, Maxfield, Frederick R, Rodriguez-Boulan, Enrique
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.04.2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; beta-Cyclodextrins - metabolism; Binding Sites; Biological Sciences; Blindness; Cells; Chemical Sciences; Chromatography, High Pressure Liquid; Computer Simulation; Fluorescence; In Vitro Techniques; Lipofuscin - isolation & purification; Lipofuscin - metabolism; Mice; Mice, Knockout; Organic chemicals; Oxidation; Oxidation-Reduction; PNAS Plus; Retina; Retinal Pigment Epithelium - metabolism; Retinoids - isolation & purification; Retinoids - metabolism; aging; residual bodies; retinopathy; lipofuscinosis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1400530111

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.