Epalrestat, an aldose reductase ihibitor, reduces the levels of Nepsilon-(carboxymethyl)lysine protein adducts and their precursors in erythrocytes from diabetic patients.

Abstract

RESULTS -In diabetic patients not treated with epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 ± 5.0 vs. 31.0 ± 5.2 U/g protein, P Ͻ 0.05) and was significantly lower in patients receiving epalrestat (33.1 ± 3.8 U/g protein, P Ͻ 0.05). Similar results were observed with 3-DG. The treatment of patients with epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 ± 5.6 at baseline vs. 34.4 ± 5.0 U/g protein, P Ͻ 0.01) along with erythrocyte 3-DG (P Ͻ 0.05), triosephosphates (P Ͻ 0.05), fructose (P Ͻ 0.05), sorbitol (P Ͻ 0.05), and plasma TBARS (P Ͻ 0.05) without changes in plasma glucose and HbA 1c levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P Ͻ 0.01) or fructose (r = 0.40, P Ͻ 0.05) levels in diabetic patients.CONCLUSIONS -The results indicate that epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.

Effect of antioxidants and ACE inhibition on chemical modification of proteins and progression of nephropathy in the streptozotocin diabetic rat

“…In support of this hypothesis, aldose reductase inhibitors, which protect against the development of nephropathy in the diabetic rat, also inhibit AGE formation [11]. Similarly, ACE inhibitors and angiotensin receptor antagonists inhibit the formation of AGE in the kidney of diabetic rats [12,13].…”

“…The AGE hypothesis has been supported by studies demonstrating that treatment with AGE inhibitors, such as aminoguanidine [1,8], OPB-9195 (2-isopropylidenehydrazono-4-oxo-thiazolidin-5-yl-acetanilide) [9] and pyridoxamine [10], has a profound inhibitory effect on the development of a range of complications, including nephropathy, in diabetic animals. However, despite the clear association between AGE and diabetic complications and the protective effects of AGE inhibitors, the results of other studies suggest that AGE are not directly involved in the pathogenesis of diabetic complications: thus aldose reductase inhibitors [11], ACE inhibitors and angiotensin receptor antagonists [12,13,14], protein kinase C inhibitors [15,16], cerivastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) [17] and benfotiamine (or thiamine) [18] have all been shown to have beneficial effects in animal models and/or clinical studies.…”

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

“…In particular, AR is involved in generation of fructose, a 10 times more potent glycation agent than glucose, as well as other AGE precursors, i.e., methylglyoxal and 3-deoxyglucosone [74,75]. ARI treatment suppresses formation of the AGE pentosidine and carboxymethyllysine [76,77] known to generate oxidative stress via interaction with their receptors [57]. Taking into consideration that diabetic kidney accumulates AGE [13], it is quite plausible that increased AR activity contributes to renal oxidative stress by promoting nonenzymatic glycation.…”

Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications

“…Aldose reductase is involved in the generation of fructose, a glycation agent that is 10 times more potent than glucose. Increased aldose reductase activity results in formation of other precursors of advanced glycation end products (AGEs), i.e., methylglyoxal and 3-deoxyglucosone (43,44), and the AGEs pentosidine and carboxymethyllysine per se (45,46). Several reports indicate that aldose reductase inhibition counteracts formation of AGEs (45,46), which are known to generate oxidative stress via interaction with their receptors (47).…”