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U. Schraermeyer, S. Schultheiss, S. Hofmeister, S. Julien; Tetrahydropyridoethers Eliminate Lipofuscin From Retinal Pigment Epithelium of Monkeys. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2786.
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© ARVO (1962-2015); The Authors (2016-present)
To test the effect of tetrahydropyridoethers (THPE) on pigment granules of the retinal pigment epithelium (RPE), monkeys (Macaca fascicularis) were orally treated with this drug for up to one year.
54 monkeys were daily treated with different concentrations of (7R, 8R, 9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imi-dazo [1,2-h] [1,7] naphthyridine between 4 weeks and one year by oral administration. 12 monkeys served as controls. Right eyes were investigated by electron microscopy, left eyes were used for immunocytochemistry and fluorescence light microscopy.
After exposure to THPE, focal depigmentation of RPE cells was observed. These sites were about 100 - 1000 µm long and their numbers were dose-dependent. Lipofuscin granules, melanosomes as well as melanolipofuscin granules disintegrated within the RPE cells and/or were released to macrophages. Different stages of pigment lysis were detected under the electron microscope. There were areas of 1000 µm2 or more in which the RPE was completely free of melanin and lipofuscin granules. Close to such depigmented RPE cells, highly pigmented macrophages identified by CD68 staining were located between Bruch’s membrane and the RPE and in the subretinal space or within the choroid.The total number of lipofuscin granules was counted in the cytoplasm of RPE cells from untreated and treated monkeys. Per 10 µm of RPE length, 7.2 ± 3.6 versus 0.07 ± 0.26 lipofuscin granules were found in RPE cells of untreated versus treated animals respectively ( p = 9,9E-08). Photoreceptors facing depigmented RPE appeared normal.
Our results demonstrate that administration of THPE induces lipofuscin elimination from RPE cells in a dose-dependent manner by degradation in RPE cells and/or transfer to macrophages. Although the mechanism is still unknown, this is an important finding which disproves the dogma of undegradable and unremovable lipofuscin from RPE cells and has the potential to serve as an active ingredient in the treatment of AMD, particularly the dry form.
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