|Name:||Kevin David Dell|
|Title:||ANTIOXIDANT INTERVENTION WITH MANGANESE(III)-SALOPHEN IN THE SELENITE CATARACT MODEL Implications For Cataract Disease|
|Degree:||Doctor of Philosophy|
|Committee Chair:||John L. Hess|
|Committee Members:||Eugene M. Gregory|
|David R. Bevan|
|Steven D. Holladay|
|Hara P. Misra|
|Keywords:||selenite, cataract, Mn-salophen, antioxidant, crystallins|
|Date of defense:||May 4, 1998|
|Availability:||Release the entire work for Virginia Tech access only.
After one year release worldwide only with written permission of the student and the advisory committee chair.
Cataract disease affects millions of people worldwide. It is characterized by the accumulation of light-scattering bodies within the lens that reduce visual acuity. Cataracts are effectively treated surgically, but at great expense, costing Medicare $3.4 billion in 1997. Development of an alternative therapy for this disease would provide medical and economic benefits. We have investigated a novel antioxidant, the superoxide scavenger Mn(III)-salophen, as a therapeutic agent in the selenite cataract model. Mn(III)-salophen has been shown to protect E. coli colonies against oxidative stress but was untested in a eukaryotic system. A total dose of 300 Ámol/kg, given IP in four equal 75 Ámol/kg doses spaced four hours apart, protects 75% of neonatal rats from nuclear cataract development five days after selenite injection. Selenite is toxic through its reaction with the endogenous antioxidant glutathione (GSH). The reduction of selenite to selenide through an intermediate, selenodiglutathione (GSSeSG) leads to generation of superoxide radical, one of several toxic oxygen species that can damage the lens. Mn(III)-salophen causes an in vitro preservation of the lifetime of GSSeSG by interrupting the reduction of selenite. We have established that the reduction of GSSeSG to selenide does not use GSH as a reducing agent, but rather depends upon electrons generated in the earlier reduction of selenite to selenodiglutathione. These electrons can be intercepted by known one-electron scavengers, arresting the metabolism of GSSeSG. Extensive proteolysis of lens crystallins and loss of calcium homeostasis occur in cataractous lenses from a rat treated with sodium selenite. The visual protection with Mn(III)-salophen is accompanied by a partial loss of the calcium homeostasis, a net increase in sodium, and calpain-mediated proteolysis of ▀-crystallins similar to lenses from animals treated with selenite alone. Although preservation of alpha-crystallins may contribute to the greater transparency in the protected lens, generalized ▀-crystallin proteolysis is insufficient for cataract formation. From these experiments we propose that Mn(III)-salophen minimizes the oxidative stress imposed upon the cell by interfering with the metabolism of selenodiglutathione. This allows the cell to compensate for the loss of cation homeostasis and prevents aggregation of proteolyzed crystallins into cataracts.
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