Date of Defense

12-6-2013

Date of Graduation

12-2013

Department

Biological Sciences

First Advisor

Cindy Linn

Second Advisor

Blair Szymczyna

Abstract

Glaucoma is an incurable ocular disease characterized by apoptotic cell death and degeneration of retinal ganglion cells (RGCs), and is one of the leading causes of blindness worldwide (Quigley and Broman, 2006; Quigley et al., 1995). While current treatments are effective at slowing vision loss, glaucoma’s multifactorial etiology has made it difficult for researchers to identify a target for treatment that will permanently halt RGC degeneration. Previous studies have proposed a glutamate-induced excitotoxic mechanism of RGC death in glaucoma, and neuroprotective agents have been investigated to prevent this effect. One agent, acetylcholine, has been shown to initiate pro-survival signaling cascades by binding to α7 nicotinic acetylcholine receptors (nAChRs) on RGCs, and prevents glutamate excitotoxicity when applied prior to glutamate insult.

PNU-282987, a drug developed by Pharmacia and Upjohn, is a specific α7 nAChR agonist that has been shown to prevent RGC death in an in vivo rat model of glaucoma in a dose-dependent manner. In this study, immunofluorescent staining techniques were utilized to investigate the effects of 2mM PNU-282987 on RGC survival when applied as an eye drop for varying amounts of time before performing a procedure to elicit glaucoma-like conditions in rats. In addition, experiments investigating the involvement of caspase-3 in the apoptotic mechanism of the in vivo glaucoma model were conducted. It was determined that 2mM PNU-282987 provided a neuroprotective effect against RGC death when applied to eyes for short periods of time prior to the onset of glaucoma-like conditions, but also resulted in apoptotic and proliferative effects when applied for extended periods of time. Additionally, it was found that caspase-3 was involved in the apoptotic mechanism associated with the in vivo model of glaucoma. The results from these studies suggest that PNU-282987 may be a valuable preventative treatment option for individuals susceptible to glaucoma development.

Access Setting

Honors Thesis-Open Access

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