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Neuroprotective Effects of PEDF on Survival and Function of Retinal Neurons In Vitro and In Vivo

James F. McGinnis

We have been interested in cellular regulatory mechanisms operating in mammalian photoreceptor cells, especially those that determine sensitivity to factors that either promote or inhibit cell death. A primary cell culture system, which supports the development and differentiation of photoreceptors, was established and used to evaluate the neurotrophic activity of PEDF. This system allows chemically defining and controlling the survival environment of photoreceptor cells, screening for factors and/or environments that promote neuron survival or death, and studying specific signal transduction pathways. Oxidative stress is thought to be an important mediator of neuronal cell death and may contribute to retinal degeneration. Hydrogen peroxide production increases in the outer nuclear layer in rats subjected to light-induced degeneration. We found that hydrogen peroxide induces the death of photoreceptor cells in culture in a time- and dose-dependent manner, whereas PEDF protects them from this apoptotic death. The in vivo light damage model was used to demonstrate that PEDF prevents the degeneration of the photoreceptors, and by electroretinography, PEDF was shown to preserve the vision of the animals. PEDF, in combination with basic fibroblast growth factor, provides better protection to the photoreceptor cells than either one alone. Using mammalian expression vectors, we have made recombinant PEDF molecules labeled with glutathione transferase, an His6 tag, or alkaline phosphatase and are evaluating their neuroprotective abilities as well as using them to identify the cells and proteins in our cultures with which PEDF interacts.