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Stefan Rakete, Mikhail Linetsky, Alexandra Dunbar, Ram H Nagaraj; A Novel Inhibitor against Advanced Glycation Endproduct Formation in Eye Tissues.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5310.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes leads to elevated glucose levels and oxidative stress. The combined effect causes higher levels of reactive carbonyls such as, methylglyoxal, which are precursors for Advanced Glycation Endproducts (AGEs). The AGE levels are generally higher in tissue and plasma proteins of diabetics than non-diabetics. In addition, the glutathione levels are reduced in diabetes, which could further promote AGE formation. Therefore, we reasoned that a systemic reduction of reactive carbonyls and elevation of glutathione levels could inhibit diabetic complications.
A novel hybrid molecule consisting of glutathione diester and mercaptoethylguanidine, hereafter named GTG, was synthesized, isolated and fully characterized. The two parts of the molecule were connected via a disulfide bond. αB-Crystallin was incubated with methylglyoxal in the presence or absence of GTG and analyzed for covalent crosslinking and AGE levels. FHL124 cells were incubated with dehydroascorbic acid in the presence or absence of GTG and analyzed for levels of GTG and its metabolites as well as α-dicarbonyls. GTG was tested in diabetic mice by i.p. injections. After 8 weeks, lenses and retinas were harvested and analyzed for AGE levels by UPLC-MS/MS.
GTG significantly reduced covalent crosslinking and AGE formation in αB-crystallin incubated with methylglyoxal. GTG was able to penetrate the plasma membrane of FHL124 cells, and it was immediately reduced and hydrolyzed to glutathione and mercaptoethylguanidine. Cells treated for 24h with dehydroascorbic acid and subsequent incubation with GTG showed a significant reduction in reactive α-dicarbonyls derived from dehydroascorbic acid. When GTG was injected into diabetic animals, AGE levels in the lens and retina were lower when compared to untreated diabetic controls.
GTG successfully blocks crosslinking and AGE formation in proteins and prevents AGE formation in eye tissues in diabetes. Thus, our novel hybrid molecule could be a promising drug candidate to reduce the formation of AGEs and inhibit long-term complications of diabetes.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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