Mechanism of the inhibitory effect of OPB-9195 [(±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] on advanced glycation end product and advanced lipoxidation end product formation

The accumulation in uremic plasma of reactive carbonyl compounds (RCO) derived from both carbohydrates and lipids ('carbonyl stress') contributes to uremic toxicity by accelerating the advanced glycation and lipoxidation of proteins. It was previously demonstrated that OPB-9195 [(±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide] inhibited the in vitro formation of advanced glycation end products (AGE) in uremic plasma. This study was designed to elucidate the mechanism of action of OPB-9195 by further delineating the AGE and advanced lipoxidation end product (ALE) precursors targeted by this drug. The inhibitory effects of OPB-9195 on the formation of two AGE (N(ε)-carboxymethyllysine and pentosidine) on bovine serum albumin incubated with various AGE precursors were examined. Inhibition of N(ε)-carboxymethyllysine and pentosidine formation with OPB-9195 was more efficient than with aminoguanidine. OPB-9195 also proved effective in blocking the carbonyl amine chemical processes involved in the formation of two ALE (malondial-dehyde-lysine and 4-hydroxynonenal-protein adduct). The efficiency of OPB-9195 was similar to that of aminoguanidine. When glucose-based peritoneal dialysis fluid was incubated in the presence of OPB-9195, a similar inhibition of AGE formation was observed. The direct effect of OPB-9195 on major glucose-derived RCO in peritoneal dialysis fluids was then evaluated. The effects of OPB-9195 could be accounted for by its ability to trap RCO. The concentrations of three major glucose-derived RCO (glyoxal, methylglyoxal, and 3-deoxyglucosone) were significantly lower in the presence of OPB-9195 than in its absence. Aminoguanidine had a similar effect. In conclusion, OPB-9195 inhibits both AGE and ALE formation, probably through its ability to trap RCO. OPB-9195 might prove to be a useful tool to inhibit some of the effects of RCO-related uremic toxicity.