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A. Dong, J. Shen, M. Krause, S. Hackett, P. A. Campochiaro; Increased Expression of Glial Cell Line-Derived Neurotrophic Factor (GDNF) in Retina Preserves Function and Reduces Cell Death From Oxidative Damage. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4500.
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Previous studies have shown that intraocular delivery of GDNF slows photoreceptor cell death in models of retinitis pigmentosa (RP). In this study, we used double transgenic mice with doxycycline-inducible expression of GDNF (Tet/opsin/GDNF and Tet/IRBP/GDNF mice) to test the effect of GDNF in models of oxidative damage-induced retinal degeneration.
The effect of GDNF was tested in 3 published models in which retinal degeneration is induced by oxidative damage secondary to hyperoxia or intraocular injection of 0.75 mM paraquat or 0.25 mM FeSO4. Outcome measures were ERG a- and b-wave amplitudes, inner and outer nuclear layer thickness, biomarkers for oxidative damage and TUNEL.
Doxycycline treatment (2 mg/ml in drinking water) of Tet/opsin/GDNF or Tet/IRBP/GDNF mice resulted in strong staining for GDNF in photoreceptors. Compared to untreated littermates, those treated with doxycycline showed significant preservation of retinal structure and function in all 3 models. The greatest effect was in mice exposed to 75% oxygen for 3 weeks in which ERG a- and b-waves were normal in doxycycline-treated mice and were reduced by 50% in untreated mice. Seven days after injection of paraquat, ERG a- and b-waves were increased by 50% and 30%, respectively in doxycycline-treated versus untreated mice, and 14 days after injection of FeSO4 there were increases of 33% and 20%, respectively. Morphologic differences, immunohistochemistry, and TUNEL corresponded with ERG changes.
Increased expression of GDNF in photoreceptors protects photoreceptors from oxidative damage. Since oxidative damage contributes to cone cell death in RP and both rod and cone cell death in AMD, GDNF is a good candidate for gene-based therapies for both of these disease processes.
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