Protection of Photoreceptors by Pigment Epithelium Derived Factor (PEDF) and Estrogen in a Mouse Model of Usher Syndrome

Abstract

Abstract: : Purpose: Usher syndrome is the most common retinitis pigmentosa syndrome. The rd5/rd5 mouse has been identified as an animal model for Usher syndrome. We have demonstrated that pigment epithelium derived factor (PEDF) and 17 beta–estradiol protects photoreceptor cells from light damage. In the present study, we tested the hypothesis that PEDF and 17 beta–estradiol can protect photoreceptors in rd5/rd5 mice. Methods: The retinas from mice homozygous rd5/rd5, heterozygous rd5/+ and wild type C57 background +/+ were compared using quantitative histology. Retinal functions were evaluated by electroretinogram. TUNEL assay, DNA fragmentation detection were used to evaluate the inhibition of apoptosis. 17 beta–estradiol or progesterone or phenyl N–tert–Butyl Nitrone (PBN) was administered once a day by intraperitoneal (IP) injection starting at postnatal days 9 (P9). PEDF or basic fibroblast growth factor (bFGF) was administered by intravitreal injection once a week starting at P14. Results: Measuring outer nuclear layer (ONL) thickness of mice homozygous for a defect of tub (rd5) gene, aged P10 to P180, by quantitative histology showed a significant reduction of ONL thickness started at P16, and progressive photoreceptor loss thereafter. By P28, 50% of photoreceptors were lost. A significant increase in TUNEL positive apoptotic cells were observed in the ONL of rd5/rd5 by P16–18. Systemic administration of 17 beta–estradiol significantly delayed photoreceptor loss during early postnatal development period but progesterone and PBN did not. Intravitreal injection of PEDF significantly reduced the loss of photoreceptors but bFGF did not. Conclusions: The data demonstrated that PEDF and 17 beta–estradiol delay photoreceptor degeneration in homozygous rd5/rd5 mice. Further investigations are needed to elucidate the mechanisms underlying this protection.

Keywords: degenerations/dystrophies • retina • neuroprotection