Pyridoxal-Aminoguanidine Adduct is More Effective than Aminoguanidine in Preventing Neuropathy and Cataract in Diabetic Rats

Abstract

We examined the ability of a pyridoxal-aminoguanidine adduct with both antiglycation and antioxidant activities in vitro to protect against neuropathy and cataract in streptozotocin-diabetic rats and compared the result with that of aminoguanidine. In vivo antiglycation and antioxidant activities were also compared between the adduct and aminoguanidine. Diabetic rats were given either of the compounds in their drinking water (9 mM) for 7 weeks. Neither compound affected body weight, blood glucose level or urine volume. The adduct, but not aminoguanidine, significantly improved motor nerve conduction velocity. The time to develop cataract was longer in adduct-treated rats than in untreated and aminoguanidine-treated rats. The increase in opacification of lenses in culture medium containing high glucose levels (55.5 mM) was more efficiently attenuated by the adduct than by aminoguanidine. Adduct and aminoguanidine similarly lowered glycated hemoglobin levels. The level of urinary 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage, and the level of liver malondialdehyde plus 4-hydroxy-2-alkenals, a marker of tissue lipid peroxidation, both of which were elevated by diabetes, were significantly reduced by the adduct but not by aminoguanidine. These findings indicate that the pyridoxal-aminoguanidine adduct is superior to aminoguanidine in preventing diabetic neuropathy and cataracts, and we suggest that this may be at least partly due to the higher antioxidant activity of the former.

Aminoguanidine - Pyridoxal-aminoguanidine adduct - Diabetic neuropathy - Diabetic cataract - Glycation - Antioxidant activity

References

• 1 Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications.  Diabetes Care. 1996;  19 257-267
• 2 van Dam P S. Oxidative stress and diabetic neuropathy: pathophysiological mechanism and treatment perspectives.  Diabetes Metab Res Rev. 2002;  18 176-184
• 3 Edelstein D, Brownlee M. Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine.  Diabetes. 1992;  41 26-29
• 4 Picard S, Parthasarathy S, Fruebis J, Witztum J L. Aminoguanidine inhibits oxidative modification of low density lipoprotein protein and the subsequent increase in uptake by macrophage scavenger receptors.  Proc Natl Acad Sci USA. 1992;  89 6876-6880
• 5 Giardino I, Fard A K, Hatchell D L, Brownlee M. Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis.  Diabetes. 1998;  47 1114-1120
• 6 Philis-Tsimikas A, Parthasarathy S, Picard S, Palinski W, Witztum J L. Aminoguanidine has both pro-oxidant and antioxidant activity toward LDL.  Arterioscler Thromb Vasc Biol. 1995;  15 367-376
• 7 Skamarauskas J T, McKay A G, Hunt J V. Aminoguanidine and its pro-oxidant effects on an experimental model of protein glycation.  Free Radic Biol Med. 1996;  21 801-812
• 8 Taguchi T, Sugiura M, Hamada Y, Miwa I. In vivo formation of a Schiff base of aminoguanidine with pyridoxal phosphate.  Biochem Pharmacol. 1998;  55 1667-1671
• 9 Taguchi T, Sugiura M, Hamada Y, Miwa I. Inhibition of advanced protein glycation by a Schiff base between aminoguanidine and pyridoxal.  Eur J Pharmacol. 1999;  378 283-289
• 10 Miyoshi H, Taguchi T, Sugiura M, Takeuchi M, Yanagisawa K, Watanabe Y, Miwa I, Makita Z, Koike T. Aminoguanidine pyridoxal adduct is superior to aminoguanidine for preventing diabetic nephrophathy in mice.  Horm Metab Res. 2002;  34 371-377
• 11 Jain S K, Lim G. Pyridoxine and pyridoxamine inhibit superoxide radicals and prevent lipid peroxidation, protein glycosylation, and (Na⁺ + K⁺)-ATPase activity reduction in high glucose-treated human erythrocytes.  Free Radic Biol Med. 2001;  30 232-237
• 12 Jain A K, Lim G, Langford M, Jain S K. Effect of high-glucose levels on protein oxidation in cultured lens cells, and in crystalline and albumin solution and its inhibition by vitamin B₆ and N-acetylcysteine: its possible relevance to cataract formation in diabetes.  Free Radic Biol Med. 2002;  33 1615-1621
• 13 Kato K, Nakayama K, Ohta M, Murakami N, Murakami K, Mizota M, Miwa I, Okuda J. Effects of novel aldose reductase inhibitors, M16209 and M16287, on streptozotocin-induced diabetic neuropathy in rats.  Eur J Pharmacol. 1991;  193 185-191
• 14 Ansari N H, Bhatnagar A, Fulep E, Khanna P, Srivastava S K. Trolox protects hyperglycemia-induced cataractogenesis in cultured rat lens.  Res Commun Chem Pathol Pharmacol. 1994;  84 93-104
• 15 Kihara M, Schmelzer J D, Poduslo J F, Curran G L, Nickander K K, Low P A. Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals.  Proc Natl Acad Sci USA. 1991;  88 6107-6111
• 16 Yagihashi S, Kamijo M, Baba M, Yagihashi N, Nagai K. Effect of aminoguanidine on functional and structural abnormalities in peripheral nerve of STZ-induced diabetic rats.  Diabetes. 1992;  41 47-52
• 17 Cameron N E, Cotter M A, Dines K, Love A. Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats.  Diabetologia. 1992;  35 946-950
• 18 Miyauchi Y, Shikama H, Takasu T. Okamiya H, Umeda M, Hirasaki E, Ohhata I, Nakayama H, Nakagawa S. Slowing of peripheral motor nerve conduction was ameliorated by aminoguanidine in streptozotocin-induced diabetic rats.  Eur J Endocrinol. 1996;  134 467-473
• 19 Dewhurst M, Omawari N, Tomlinson D R. Aminoguanidine-effects on endoneurial vasoactive nitric oxide and on motor nerve conduction velocity in control and streptozotocin-diabetic rats.  Br J Pharmacol. 1997;  120 593-598
• 20 Wada R, Sugo M, Nakano M, Yagihashi S. Only limited effects of aminoguanidine treatment on peripheral nerve function, (Na⁺, K⁺)-ATPase activity and thrombomodulin expression in streptozotocin-induced diabetic rats.  Diabetologia. 1999;  42 743-747
• 21 Swamy-Mruthinti S, Green K, Abraham E C. Inhibition of cataracts in moderately diabetic rats by aminoguanidine.  Exp Eye Res. 1996;  62 505-510
• 22 Agardh E, Hultberg B, Agardh C-D. Effects of inhibition of glycation and oxidative stress on the development of cataract and retinal vessel abnormalities in diabetic rats.  Curr Eye Res. 2000;  21 543-549
• 23 Azal Ö, Yönem A, Güler S, Çakir A, Baydar A, Çorakçi A, Kutlu M. Effects of aminoguanidine and tolrestat on the development of ocular and renal structural changes in experimental diabetic rats.  Diab Obes Metab. 2002;  4 75-79
• 24 Edelstein D, Brownlee M. Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine.  Diabetes. 1992;  41 26-29
• 25 Jain S K, Palmer M. The effect of oxygen radicals metabolites and vitamin E on glycosylation of proteins.  Free Radic Biol Med. 1997;  22 593-596
• 26 Ross W M, Creighton M O, Trevithick J R, Stewart-DeHaan J P, Sanwal M. Modelling cortical cataractogenesis IV. Induction by glucose in vitro or in diabetic rats: prevention and reversal by glutathione.  Exp Eye Res. 1983;  37 559-573
• 27 Srivastava S K, Ansari N H. Prevention of sugar-induced cataractogenesis in rats by butylated hydroxytoluene.  Diabetes. 1988;  37 1505-1508