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X. Fan, C. Strauch, V. M. Monnier; Nucleophilic Compounds Block Advanced Glycation End Product (AGE) Formation From Ascorbic Acid in the hSVCT2-enA Transgenic Mouse Model of Lenticular Aging. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3184.
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© ARVO (1962-2015); The Authors (2016-present)
Senile cataracts are associated with progressive oxidation, fragmentation, cross-linking, insolubilization, and yellow pigmentation of lens crystallins. We formerly hypothesized that the Maillard reaction, which leads to browning and aroma development during the baking of foods, occurs between the lens proteins and the highly reactive oxidation products of ascorbic acid (ASA). To prove the concept we engineered a mouse that selectively overexpresses the human vitamin C transporter SVCT2 in the lens, and displays ASA levels identical with those of the human lens (PNAS 103:16912, 2006). At 12 mos of age all AGEs attributable to ASA (pentosidine, CML, K2P, vesperlysine A and total fluorescence) were highly significantly increased, and the lenses were yellow like those from a 70 yrs old human lens. We now present the first pharmacological intervention study against ASA-derived AGE formation in the hSVCT2-ΔenαA transgenic mouse.
Five groups of two months old mice (10 mice/group) were fed with 0.1% of candidate inhibitors, aminoguanidine (AG), pyridoxamine (PM), penicillamine (PA) and nucleophilic inhibitors 1 (NI-1) and 2 (NI-2), which were incorporated into standard diet until 9 months old with age matched controls. AGEs in lens proteins were determined using HPLC, LC-MS or GC-MS.
After exposure to these inhibitors, the mice showed no alterations in body weight, food intake, glutathione level and glucose-derived glycation. Treatment with NI-1 and NI-2 resulted in a significant decrease in lens protein fluorescence at ex335/em385 (p=0.05, 0.02, respectively) and ex370/em440 (p=0.04, 0.004, respectively), but no effect from the other inhibitors. At 7 months treatment, NI-1 and NI-2, but not the other drugs, induced a 50 % reduction in pentosidine level (p=0.04, 0.003 respectively). Significant reduction of carboxymethyllysine (CML) level (p=0.007) was caused by NI-1. NI-1 treated mice also displayed reduced carboxyethyllysine (CEL) level (p=n.s), and both NI-1 and NI-2 showed reduced K2P level compared with age matched controls (p=n.s).
These results show that the lenticular formation of ASA derived glycation products can be pharmacologically blocked using the nucleophilic inhibitors NI-1 & NI-2. Dose effect and HTS studies are being carried out to define optimal prevention conditions with an eye toward future clinical application.
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