Biological effects of aminoguanidine: An update

Abstract

Aminoguanidine (AMG) was prepared more than 100 years ago. During the last 10 years two important effects of AMG have been discovered which have made this molecule attract a lot of interest. Firstly, AMG inhibits, in vitro and in vivo, formation of highly reactive advanced glycosylation end products (AGEs) associated with pathogenesis of secondary complications to diabetes and with cardiovascular changes in aging. AMG ameliorates various complications to diabetes and prevents age related arterial stiffening and cardiac hypertrophy, effects probably dependent on inhibition of AGEs formation. Secondly, AMG inhibits NO synthase particularly the inducible NO synthase isoform making AMG an important pharmacological tool. The inducible NO synthase isoform is associated with production of large quantities of NO synthase in response to e. g. cytokines. When these effects of AMG were disclosed it had already been known for many years that AMG, in nM concentrations, inhibits diamine oxidase. This enzyme catalyzes degradation of biologically active diamines such as histamine and putrescine. Data obtained from studies using AMG should be interpreted with precaution since this substance interferes with several important regulatory systems. In this review these important targets for AMG are addressed.

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

“…Because of the correlations demonstrated between proteinuria, albuminuria, CML in skin collagen and plasma triglyceride concentration in an earlier study [10], we proposed that lipids may be an important source of chemical modification of tissue proteins in the diabetic rat [43]. Indeed, increases in CML, CEL, MDA-lysine, 4-hydroxynonenal-lysine and pentosidine were also observed in the hyperlipidaemic, Zucker obese, non-diabetic rat [8]. Interestingly, vitamin E had a somewhat greater lipid-lowering effect than enalapril or lipoic acid, which was consistent with their order of efficacy in inhibiting renal disease and AGE/ALE formation, although in all cases this lipid-lowering effect was lower than that of pyridoxamine.…”

“…The increase in AGE formation in diabetes is variously attributed to: (i) the increase in glycaemia alone [3]; (ii) an increase in oxidative stress, combined with the increase in glycaemia [4,5]; (iii) an increase in carbonyl stress, resulting from overproduction of reactive dicarbonyl intermediates or defects in their detoxification pathways [6]; and (iv) an alternative hypothesis proposing that lipids are the primary source of chemical modification of proteins and that hyperglycaemia, with concurrent hyperlipidaemia, exacerbates formation of advanced lipoxidation end-products (ALE) in tissue proteins in diabetes [7]. 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.…”

Simple non-invasive assessment of advanced glycation endproduct accumulation

“…Apart from plasma AGE and haemoglobin-AGE assays, few tools are currently available for monitoring the effects of interventions aimed at reducing AGE accumulation, such as aminoguanidine or AGE-breakers [16,17,18]. The AFR could be a promising alternative for monitoring interventions for the following reasons: (i) disparate changes between plasma and tissue AGE levels may occur [19], and tissue AGE accumulation may be more relevant to the development of tissue damage than plasma levels; (ii) current plasma AGE assays are time-consuming and the results can be difficult to reproduce or standardise between laboratories.…”

“…In a DCCT substudy, skin AGE levels explained 19 to 36% of the variance in the incidence of long-term diabetic complications in intensively treated patients, and 14 to 51% in conventionally treated patients [8]. These associations remained after adjustment for HbA 1 c. Experimentally, prevention of AGE accumulation has been shown to reduce the development of several diabetic complications [16,17,18].…”

Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

“…It has been shown in vivo to prevent disease states characterized by the pathological overproduction of NO, such as diabetic complications [9] , age-related arterial stiffening, cardiac hypertrophy [10] and also tumors (including cholangiocarcinoma [11] and gastric cancer [12] ). These effects of AG are exerted by modulating proliferation [12] , apoptosis [12] , angiogenesis [12] , by the production of free radicals [12] and by preventing the formation of advanced glycation end products (AGEs) [13,14] .…”