Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium.
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.
Margaret Dyson Vision Research Institute, Department of Biochemistry, and Department of Physiology, Weill Cornell Medical College of Cornell University, New York, NY 10065.
Marcelo M
MM
Nociari
Guillermo L
GL
Lehmann
Andres E
AE
Perez Bay
Roxana A
RA
Radu
Zhichun
Z
Jiang
Shelby
S
Goicochea
Ryan
R
Schreiner
J David
JD
Warren
Jufang
J
Shan
Ségolène
S
Adam de Beaumais
Mickaël
M
Ménand
Matthieu
M
Sollogoub
Frederick R
FR
Maxfield
Enrique
E
Rodriguez-Boulan
D000818:Animals; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D005453:Fluorescence; D066298:In Vitro Techniques; D008062:Lipofuscin / Q000302:isolation & purification / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D012176:Retinoids / Q000302:isolation & purification / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000378:metabolism*
D008062:Lipofuscin; D012176:Retinoids; D047392:beta-Cyclodextrins
aging; lipofuscinosis; residual bodies; retinopathy