Effect Of A Schiff Base Of Pyridoxal And Aminoguanidine On Diabetic Complications

Aminoguanidine (AG), having both anti-glycation activity and antioxidant activity, has been regarded as one of the most promising compounds for the treatment of diabetic complications. On the other hand, however, AG is known to have pro-oxidant activity in vitro. In addition, liver pyridoxal phosphate levels in normal mice were severely reduced by AG administration.With the goal of making a possible improvement of AG, we synthesized a Schiff base of pyridoxal and aminoguanidine (PL-AG). PL-AG showed in vitro anti-glycation activity comparable to that of AG and, importantly, did not affect liver pyridoxal phosphate levels. We also reported that PL-AG prevented nephropathy in streptozotocin-diabetic mice more effectively than AG.In the present study, we additionally investigated the inhibitory activity of PL-AG in comparison with AG against in vitro and in vivo oxidation. PL-AG was more potent than AG and reference compounds such as pyridoxal and pyridoxamine in any of the 8 antioxidant activities examined in vitro, i.e., hydroxyl radical-scavenging, hydrogen peroxide-scavenging, superoxide radical-scavenging, ascorbate-autoxidation inhibitory, benzoate-oxidation inhibitory, LDL-oxidation inhibitory, plasma lipid-oxidation inhibitory, erythrocyte membrane lipid-oxidation inhibitory activities. Unlike AG, PL-AG did not show the pro-oxidant activity. The inhibitory activity of PL-AG against lipid peroxidation in diabetic rats was higher than that of AG. A fluorescent substance different from PL-AG was present in the plasma and urine of rats treated with PL-AG. The chemical structure of the substance, i.e. oxidized PL-AG, was determined by a combination of nuclear magnetic resonance, mass, and infrared spectrometry. AG dramatically decreased the pyridoxal phosphate level of diabetic rat liver, whereas PL-AG only moderately affected it. The increase in opacification of lenses in culture medium containing high glucose was efficiently attenuated by PL-AG than by AG. PL-AG was more potent than AG in preventing cataract and neuropathy in streptozotocin-induced diabetic rats. The time to develop cataract was longer in PL-AG treated rats than in untreated or AG treated rats. Treatment with PL-AG, but not that with AG, significantly improved motor nerve conduction velocity. PL-AG and AG similarly ameliorated glycated hemoglobin levels. The level of urinary 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage, which was elevated by diabetes, was reduced by PL-AG but not by AG.The results suggest that PL-AG is more promising for the treatment of diabetic complications than AG.