Date of Award

1-2011

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. Cindy Linn

Abstract

The purpose of this dissertation is to assess the potential neuroprotective effect of an alpha7 nAChR agonist, PNU-282987, and modulator, PNU-120596, in an in vitro model of excitotoxicity and an in vivo model of acute glaucoma. In in vitro studies, retinas obtained from Long Evans rats were cultured using various concentrations of the PNU compounds to analyze neuroprotection against glutamate-induced excitotoxicity. After 3 days in culture, RGCs were identified using an antibody against Thy 1.1, visualized using a fluorescent dye and quantified. In culture, glutamate significantly decreased the number of RGCs. However, if either PNU compound was introduced before the glutamate insult, higher survival of cells was observed. In in vivo studies, PNU compounds were injected intravitreally to determine their potential neuroprotective effect in a rat glaucoma model. Following treatments with PNU compounds, surgery was performed to induce glaucoma-conditions by injecting 0.05ml of 2mM NaCl into the episcleral veins of right eyes in each rat. The left eye in each rat was left untreated. After one month, rats were euthanized, retinas were removed, flat mounted, fixed and nuclei were stained with cresyl violet or immunostained with an antibody against Thy 1.1. Stained nuclei in the RGC layer in glaucoma-induced retinas were counted and compared to cell counts from untreated retinas. The surgery to induce glaucoma-like conditions caused a significant loss of cells in the RGC layer within 1 month after surgery. However, this effect was eliminated if either PNU compound was injected into the right eye an hour before surgery. The results from this thesis support the hypothesis that the alpha7 agonist, PNU-282987 and modulator, PNU-120596, have a neuroprotective effect in the rat retina. PNU-282987 and PNU-120596 may be viable candidates for future therapeutic pretreatment of glaucoma.

Access Setting

Dissertation-Open Access

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