Aminoguanidine

An orally active xenobiotic drug which greatly inhibits the formation of Advanced Glycation End-Products (AGEs) and is used in Europe for diabetic therapy.


Below we present a summary of the major research results concerning aminoguanidine (AG) taken from published studies in the peer-reviewed literature. We give evidence that its highly beneficial effects are likely caused by the ability of aminoguanidine, by whatever process, to inhibit glycation leading to the formation of AGEs. We also examine the evidence that AG is toxic and provide evidence and reasons that this potential toxicity can be fully mediated by supplemental pyridoxamine (or other B6 vitamers). Aminoguanidine under the trade name Pimagedine has been under clinical evaluation by Alteon Inc, since 1993.

Safety and Interactions

  1. "Administration of aminoguanidine caused the formation of a Schiff base adduct between aminoguanidine and pyridoxal phosphate in the liver and kidney of mice and a concomitant decrease in the amount of liver pyridoxal phosphate. In order to avoid this problem, we developed an aminoguanidine pyridoxal Schiff base adduct and examined its efficacy in vitro as well as in a model of diabetic nephropathy. ... These findings suggest that aminoguanidine pyridoxal adduct may be superior to aminoguanidine, as it not only prevents vitamin B6 deficiency but is also better at controlling diabetic nephropathy, as this adduct inhibits oxidation as well as glycation."R1,R2
  2. "Diabetes remarkably increased plasma glucose, fructosamine and dyslipidaemia (increased TC, LDLC and decreased HDLC). Oxidative markers like oxidative susceptibility of LDL, catalase activity and NO levels were greatly enhanced. Finally, it increased the synthesis and release of cytokine (IL-1beta and TNF alpha). Treatment of diabetic rats with AG and omega 3FAs markedly reduced the above mentioned parameters. Combined form therapy has a better effect regarding oxidative cell markers, specifically NO level. Finally, omega 3FAs coadministration with AG nearly restored the atrophy of islets of Langerhan's and the peripheral lymphocytic infiltration compared to diabetic and AG treated groups. In conclusion, there is a direct correlation between glycation, oxidative stress and cytokine production with increased propensity of microvascular disorder in STZ diabetic rats. omega 3FA administration with AGE receptor blocker may represent a possible avenue of research for therapeutics directed for alleviating the complication associated with diabetes."R
  3. "Effects of aminoguanidine (AG) on binding of glucose and pyridoxal phosphate (PLP) to albumin, and on glycation reaction of cytosolic aspartate aminotransferase (cAST) were examined in an in vitro system. AG was found to inhibit not only glycation of albumin but binding of PLP to albumin, indicating that distribution of PLP into tissues is inhibited by AG. AG bound to PLP directly to produce a new compound, and in this manner AG inhibited cAST activity. AG could also inhibit glycation of cAST and the extent of inhibition was varied with sugars used. It appears that, although AG is a useful inhibitor of glycation proteins, it may be toxic from the viewpoints of vitamin B6 as an essential nutrient and also PLP-dependent enzymes."R
  4. "Aminoguanidine (AG) has been proposed as a drug of potential benefit in prophylaxis of the complications of diabetes. We show here that AG irreversibly inhibits catalase with an efficacy similar to aminotriazole. AG also produces hydrogen peroxide, in a transition metal-catalysed process which may be partially dependent upon prior hydrolysis of AG to semicarbazide and hydrazine. These observations may be of importance in proposals for the long term administration of AG in diabetes."R
  5. "In order to evaluate the possible toxicity of aminoguanidine on peripheral nerves, Sprague-Dawley rats received aminoguanidine intraperitoneally in dosages of 0, 50, 100, and 300 mg/kg per day for 3 months. Only rats receiving the highest dosages developed acute and chronic behavioral changes and had decreased weight gain. Minor hepatic dysfunction also was observed in this group. Teased-fiber abnormalities were not significantly more frequent in the highest dosage group than in controls. Likewise, a significant morphometric abnormality was not found for the peroneal nerve. Mild changes were found in the highest dosage group compared to the control group in the sural nerve (increased fiber density, decreased myelin area). We interpret the small morphometric differences for the sural nerve as due to maldevelopment. We found no evidence that aminoguanidine at a high dosage (300 mg/kg per day) caused fiber degeneration or demyelination."R

Proven Benefits

  1. "Decreased DDAH [dimethylarginine dimethylaminohydrolase] activity and elevated endogenous ADMA [asymmetric dimethylarginine] is implicated in endothelial dysfunction of rats exposed to GBSA [glycosylated bovine serum albumin]. Aminoguanidine can protect endothelium of rat aorta against injury induced by GBSA both in vitro and in vivo."R
  2. "We conclude that long-term administration of AG to the [Streptozotocin] treated rats imparts significant protection against the diabetes-derived deterioration in vascular dynamics, at least partly through inhibition of the AGEs accumulation on collagen in the arterial wall."R
  3. "The presented data provide evidence that AG is preventive against corneal alterations in experimental diabetes [in Streptozotocin treated rats]."R
  4. "aminoguanidine improves wound healing, restores growth factor TGF-beta1 expression, and preserves collagen ultra structure [in diabetic rats similar to healthy rats]"R
  5. "The enzymatic activities of CAT (catalase), GPx (gluthatione [Sp] peroxidase), GR (gluthatione [Sp] reductase) and GSH (reduced gluthatione [Sp]) were increased in the blood of healthy rats subjected to endurance training, whereas, in diabetic rats the activities of CAT, GPx and GR were unaltered by similar training... The administration of aminoguanidine (an inhibitor of glycation reactions) in the drinking water increased the activities of CAT, GPx and GR"R
  6. "Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-alpha [protein kinase C] as well as in the -betaI, -betaII, and -epsilon isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-alpha from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor [VEGF] and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-alpha, in the diabetic kidney, which can be directly inhibited by ALT-711."R
  7. "Diabetic [mice] received no treatment or treatment with the inhibitor of AGE formation aminoguanidine (1 g/kg per d) or the cross-link breaker [4,5-dimethyl-3-(2-oxo2-phenylethyl)-thiazolium chloride] ALT-711, which cleaves preformed AGE (20 mg/kg per d) for 20 wk.... The two treatments, which attenuated renal AGE accumulation in a disparate manner, were associated with less albuminuria, structural injury, macrophage infiltration, TGF-beta1, and collagen expression."R
  8. "in streptozotocin-induced diabetic apolipoprotein E-deficient (apoE-/-) mice... ALT-711 and AG demonstrated the ability to reduce vascular AGE accumulation in addition to attenuating atherosclerosis in these diabetic mice."R
  9. "In rats ... These results suggest that aminoguanidine [(30 micromol/kg, i.v.; 30 min before the start of heat exposure) pretreatment] protects against heatstroke-induced intracranial hypertension and cerebral ischemic injury."R
  10. "[In rats] Aminoguanidine (100 mg/kg i.p., daily for 8 days) treatment significantly reduced all these inflammatory parameters, indicating that it protects against the tissue damage associated with periodontitis by reducing nitric oxide production and oxidative stress."R
  11. "In this [rat] model, the pharmacological use of an inhibitor of NOS-2 [nitric oxide synthase], aminoguanidine, significantly prevents the loss of retinal ganglion cells. A well-tolerated pharmacological inhibitor of NOS-2, perhaps orally or locally delivered, is a reasonable candidate for a neuroprotective agent for treating glaucoma."R
  12. "Exposure to blast at 20 kPa resulted in a significant performance decrement on rotametric and grip-strength tests in rats treated with normal saline. In contrast, animals receiving AG either prophylactically before or after the blast seemed unaffected by the same blast. This finding also correlates well with histologic examination that showed a reduction in degenerating cortical neurons in AG-treated rats compared with those receiving saline injection. CONCLUSION: It is thus suggested that AG could play a neuroprotective role in rats subjected to blast exposure."R
  13. "Several agents have been shown to interfere with the formation of AGE or AGE precursors, bind to tissue receptors, or promote breakdown of deposits. The first and most studied inhibitor, aminoguanidine, has shown extensive beneficial effects in experimental models of diabetic vascular damage, recently entering phase I-III clinical investigation."R
  14. "Incubation of rat tail tendon (RTT) with 100 mmol/l glucose showed an increase in collagen cross-linking expressed as an increase in shrinkage temperature (T(s)). Addition of aminoguanidine (AG), an inhibitor of AGE formation, prior to glucose incubation showed a slower increase of the amount of glucose-derived cross-linking. Replacing glucose with ribose showed a quicker increase in cross-linking and less effect on cross-linking by adding aminoguanidine, demonstrating the higher reactivity of pentoses above hexoses."R
  15. In streptozotocin-diabetic rats treated with pyridoxamine and in parallel with aminoguanidine, the prototype AGE inhibitor, pyridoxamine significantly inhibited the increase in albuminuria, plasma creatinine, hyperlipidemia and plasma lactate/pyruvate ratio without an effect on blood glucose or glycated hemoglobin. AGE/ALEs, fluorescence and cross-linking of skin collagen increased approximately twofold in diabetic versus control rats after seven months of diabetes. Pyridoxamine caused a significant (25 to 50%) decrease in the advanced glycation and lipoxidation end products (AGE/ALEs), carboxymethyllysine and carboxyethyllysine, in cross-linking and fluorescence in skin collagen of diabetic rats, but did not affect pentosidine. Pyridoxamine and aminoguanidine had similar effects on parameters measured, supporting a mechanism of action involving AGE/ALE inhibition.R
  16. The following are clinical trials in which aminoguanidine has proven to be beneficial.
  17. "Atherosclerosis may be viewed as an age-related disease initiated by nonenzymatic, chemical reactions in a biological system. The peroxidation of lipids in lipoproteins in the vascular wall leads to local production of reactive carbonyl species that mediate recruitment of macrophages, cellular activation and proliferation, and chemical modification of vascular proteins by advanced lipoxidation end-products (ALEs). The ALEs and their precursors affect the structure and function of the vascular wall, setting the stage for atherogenesis. The increased risk for atherosclerosis in diabetes may result from additional carbonyl production from carbohydrates and additional chemical modification of proteins by advanced glycation end-products (AGEs). Failure to maintain homeostasis and the increase in oxidizable substrate (lipid) alone, rather than oxidative stress, is the likely source of the increase in reactive carbonyl precursors and the resultant ALEs and AGEs in atherosclerosis. Nucleophilic AGE-inhibitors, such as aminoguanidine and pyridoxamine, which trap reactive carbonyls and inhibit the formation of AGEs in diabetes, also trap bioactive lipids and precursors of ALEs in atherosclerosis. These drugs should be effective in retarding the development of atherosclerosis, even in nondiabetic patients."R

Potential Benefits and Mechanisms of Action

  1. "Cell treatment with dicarbonyl sugars also disrupted the HDL-mediated cell cholesterol efflux, but this was prevented by AMG [aminoguanidine] and MF [metformin] that reduced CML [Carboxymethyllysine, one form of AGE] formation. By adversely impairing the HDL-mediated cell cholesterol removal rate, AGE-albumin and cell glycoxidation could facilitate the development of premature atherosclerosis in diabetes mellitus (DM) and in other diseases associated with carbonyl and oxidative stress like in chronic uremia. Thus, drugs that prevent AGE formation may be useful to correct disturbances in cell cholesterol transport."R
  2. AG is likely to have antiaging properties similar to carnosine potentiated by its antiglycation metabolic actions.R
  3. "Aminoguanidine was the most potent inhibitor of nonenzymatic glycosylation and 54% or 85% inhibition occurred when 5 or 50 mM aminoguanidine, respectively, was present in the incubation mixture containing 20 mM glucose. A major effect of aminoguanidine was to lower the free glucose concentration in the incubation mixture by a direct reaction with glucose as judged by thin layer chromatography."R

Negative Results and Limitations

  1. "in diabetic rats.... Treatment with ALT-711, but not with aminoguanidine, reversed ED [erectile dysfunction] and nNOS depletion and reduced serum and penile tissue AGE levels."R
  2. AG was evaluated for its effects in preventing age-related collagen cross-linking, glycation, and glycoxidation in Fischer 344 rats by administering the drug in their drinking water at 1 g/l from the time they were 6 months until they were 24 months of age. Tail tendon break time (TBT), glycation, and glycoxidation all increased significantly with age. However, except for a modest decrease of TBT at all ages that approached significance, AG had no effect on collagen glycation or glycoxidation. These results are important because they suggest that alpha,beta-dicarbonyl compounds that can be trapped by aminoguanidine do not play a major role in collagen aging in the rat. Instead, post-Amadori pathways involving oxidative or nonoxidative fragmentation of the Amadori product emerge as the more likely mechanism of collagen cross-linking in aging.R
  3. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML [N(epsilon)-(carboxymethyl)lysine] in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation.R

Reviews and Additional Reading

  1. "Several approaches have been used to inhibit tissue accumulation of AGEs in diabetes, including inhibitors of AGE formation such as aminoguanidine, ALT 946, and pyridoxamine-or putative cross-link breakers such as ALT 711. Alternative interventions have also included the administration of a soluble receptor for RAGE, sRAGE, thus capturing circulating AGEs and preventing them from binding to the cell-bound full-length receptor RAGE, thereby inhibiting the proinflammatory and profibrotic response following AGE-RAGE binding. In this review we summarize the evidence for such antiglycation therapies in retarding or delaying the development and progression of diabetes-associated atherosclerosis and renal disease while focusing on interventional strategies inhibiting AGE accumulation. In summary, all approaches have been shown to confer some degree of antiatherosclerotic and renoprotective effects, albeit to different degrees and by different mechanisms."R
  2. "novel therapeutic agents to reduce the accumulation of AGEs in diabetes have gained interest as potential cardioprotective approaches. A variety of agents have been developed which are examined in detail in this review. These include aminoguanidine, ALT-946, pyridoxamine, benfotiamine, OPB-9195, alagebrium chloride, N-phenacylthiazolium bromide and LR-90."R
  3. "This review summarises the renoprotective effect of inhibitors of AGE formation, including aminoguanidine, and of cross-link breakers, including ALT-711, on experimental diabetic nephropathy and on mesenteric vascular hypertrophy."R
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