Several retinal dystrophies are characterized by the accumulation of lipofuscin, pigmented granular debris, in the retinal pigment epithelium (RPE). The first molecular component of lipofuscin to be identified is the bis-retinoid pyridinium compound A2E. The cytotoxicity of A2E mediated by blue light irradiation has been reported in the literature. A2E has also been observed to undergo oxidation in RPE cells. The structural characterization of A2E oxidation products reveals that the oxidation of A2E results in the formation of relatively stable furanoid oxides and very reactive aldehydes. In the present work, the antioxidant properties of glutathione (GSH) have been studied and GSH is found to inhibit A2E oxidation; several tentative products of this reaction are reported. Our studies also demonstrate that A2E derivatives rapidly react with GSH, which may cause disruption of redox status in aged RPE cells, consequently causing them to be more susceptible to oxidative stress.
The accumulation of lipid-like material in Bruch's membrane (BM) is characteristic of age-related maculopathy and this lipid-like material may be related to lipofuscin. It has been hypothesized that abnormal lipid accumulation in BM blocks nutrient and waste circulation between the RPE and the choriocapillaris. In addition, there is strong evidence that this plays a role in chronic inflammation of the tissue. We have identified a nitrated form of A2E that is present in BM from older humans but not in RPE and only in barely detectable amounts from young BM. This is the first molecular biomarker of inflammation to be observed in BM since there is an overproduction of NO during inflammation.
|Advisor:||Gaillard, Elizabeth R.|
|Commitee:||Dillon, James, Hosmane, Narayan S.|
|School:||Northern Illinois University|
|Department:||Chemistry and Biochemistry|
|School Location:||United States -- Illinois|
|Source:||MAI 47/03M, Masters Abstracts International|
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