Glutathione Monoesters to Counteract Ocular Chemical Injury

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): The goal of this project is to test the hypothesis that glutathione monoesters (GME) can be used as a first line of defense against ocular toxicity caused by the chemical warfare agent sulfur mustard (SM). This vesicant causes severe ocular injuries, including eyelid burns, pain, prolonged conjunctivitis, corneal opacity, corneal ulceratin and, in severe cases, blindness. Oxidative stress, apoptosis, inflammation and proteolysis are among the known mechanisms involved in the pathogenesis of tissue injury induced by SM. It is well established that SM-induced toxicity is associated with depletion of glutathione (GSH) and that supplementation with either GSH or N-acetylcysteine (NAC) may prevent and/or protect against SM-induced cellular injury in cell culture experiments. While these findings are encouraging, the approach of using GSH or NAC as a treatment has several drawbacks, including the limited bioavailability of GSH and NAC as well as that the possibility of NAC acting as pro-oxidant. These inherent problems diminish substantially the potential of using either GSH or NAC as therapeutic agents for protection against ocular injury caused by SM. We propose to test the hypothesis that GME protects the eye against damage caused by exposure to SM. Monoesters of GSH, in which the glycine carboxyl group of the GSH tripeptide is esterified, have been shown to be effective GSH delivery agents. They are readily transported into cells and then enzymatically cleaved by intracellular esterases to release GSH. In vitro and in vivo studies have shown that GME treatment results in elevations in total cellular GSH levels that exceed those achieved by GSH treatment alone. Hence, GME obviates the cellular uptake challenges associated with using GSH alone as a treatment strategy for chemical warfare agents. The specific goal of this project is to determine the efficacy of GME in treating ocular tissue damage induced by SM. This will involve the use of a novel ex vivo isolated rabbit eye (IRE) model to measure the effect of GME treatment on the depth of injury (DoI) following SM analog exposure. Successful completion of the experiments outlined in this proposal will provide important feasibility data that are anticipated to support the expansion of this project to examining the protective effects of GME against SM in live animals.