Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats.
Age-related macular degeneration, a neurodegenerative and vascular retinal disease, is the most common cause of blindness in the Western countries. Evidence accumulates that target of rapamycin is involved in aging and age-related diseases, including neurodegeneration. The target of rapamycin inhibitor, rapamycin, suppresses the senescent cell phenotype and extends life span in diverse species, including mice. Rapamycin decreases senescence-associated phenotypes in retinal pigment epithelial cells in culture. Herein, we investigated the effect of rapamycin on spontaneous retinopathy in senescence-accelerated OXYS rats, an animal model of age-related macular degeneration. Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, which was given orally as a food mixture. In a dose-dependent manner, rapamycin decreased the incidence and severity of retinopathy. Rapamycin improved some (but not all) histological abnormalities associated with retinopathy. Thus, in retinal pigment epithelial cell layers, rapamycin decreased nuclei heterogeneity and normalized intervals between nuclei. In photoreceptor cells, associated neurons, and radial glial cells, rapamycin prevented nuclear and cellular pyknosis. More important, rapamycin prevented destruction of ganglionar neurons in the retina. Rapamycin did not exert any adverse effects on the retina in control disease-free Wistar rats. Taken together, our data suggest the therapeutic potential of rapamycin for treatment and prevention of retinopathy.
Institute of Cytology and Genetics, The Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia.
Nataliya G
NG
Kolosova
Natalia A
NA
Muraleva
Anna A
AA
Zhdankina
Natalia A
NA
Stefanova
Anzhela Z
AZ
Fursova
Mikhail V
MV
Blagosklonny
D000818:Animals; D002829:Choroid / Q000187:drug effects / Q000473:pathology; D008268:Macular Degeneration / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000473:pathology; D038601:Ribosomal Protein S6 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D038601:Ribosomal Protein S6; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus