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Yujuan Wang, Defen Shen, Jingsheng Tuo, Preeti Subramanian, S. Patricia Becerra, Chi-Chao Chan; Pigment Epithelium-derived Factor Inhibits Neuroretinal Apoptosis in a Murine Model of Focal Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4278.
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Age-related macular degeneration (AMD) is a neurodegenerative disease that causes irreversible central vision loss in the elderly. Apoptosis of retinal cells plays a critical role in the pathogenesis of AMD. The Ccl2-/-/Cx3cr1-/- mice on rd8 background (DKO) are generated as an AMD model, developing AMD-like retinal lesions. Pigment epithelium-derived factor (PEDF) is a potent neurotrophic and neuroprotective glycoprotein that protects the RPE, photoreceptors and neurons against cell death by a variety of pathological insults. In this study, we evaluated the effects of PEDF on the retinal lesions of the DKO mice.
The right eyes of 6-week-old DKO mice were intravitreously injected with highly purified recombinant human PEDF protein (1 µg), followed by a second subconjunctival injection of PEDF (3 µg) 4 weeks later. The left eyes were untreated and served as controls. Fundoscopic pictures were taken and scored before injection and 4 weeks after each injection. The mice were sacrificed 4 weeks after the second injection. Ocular histopathology was examined. Retinal A2E, a major component of lipofuscin, was measured by HPLC. Apoptosis related transcripts were measured by quantitative RT-PCR and compared between the treated and control eyes.
Two independent experiments were performed and yielded similar data. The series fundoscopy for 8 weeks showed a tendency of slower progression or attenuation of the focal, deep retinal lesions in the PEDF treated eyes compared with the control eyes. Among 24 pairs of eyes, average clinical scores of progression are 1.14±0.12 in the treated eyes and 1.32±0.14 in the control (p=0.08), respectively. This observation was confirmed by histology illustrating fewer and/or smaller photoreceptor lesions in the treated eyes than the control. A2E levels were significantly lower in the treated eyes than the control eyes (14±1.3 vs 21.3±1.6, p<0.01). Quantitative RT-PCR showed up-regulated expression of FasL andFas transcripts in the treated eyes compared with the control eyes.
PEDF potently stabilizes photoreceptor degeneration in DKO mice. One of the protective mechanisms may be via antiapoptotic pathway. The neuroprotective effect of PEDF represents a novel approach for potential treatment of AMD.
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