Aminoguanidine scientific update |
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Br J Pharmacol. 2008 Jun;154(4):758-64.
Wu MS, Liang JT, Lin YD, Wu ET, Tseng YZ, Chang KC.
Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Aminoguanidine prevents the impairment of cardiac pumping mechanics in rats with streptozotocin and nicotinamide-induced type 2 diabetes.
Aminoguanidine is best to prevent the impairment of cardiac pumping mechanics in rats. All the rats tested in the study have streptozotocin and nicotinamide-induced type 2 diabetes. Aminoguanidine therapy has the capability to prevent contractile dysfunction of the heart and the augmentation in LV internal resistance in rats.
BACKGROUND AND PURPOSE: Aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been shown to prevent arterial stiffening and cardiac hypertrophy in streptozotocin (STZ) and nicotinamide (NA)-induced type 2 diabetes in rats. Our aims were to examine whether AG produced benefits on cardiac pumping mechanics in the STZ and NA-treated animals in terms of maximal systolic elastance (E(max)) and theoretical maximum flow (Q(max)). EXPERIMENTAL APPROACH :After induction of type 2 diabetes, rats received daily injections of AG (50 mg kg(-1), i.p.) for 8 weeks and were compared with age-matched, untreated, diabetic controls. Left ventricular (LV) pressure and ascending aortic flow signals were recorded to calculate E(max) and Q(max), using the elastance-resistance model. Physically, E(max) reflects the contractility of the myocardium as an intact heart, whereas Q(max) has an inverse relationship with the LV internal resistance. Key results: Both type 2 diabetes and AG affected E(max) and Q(max), and there was an interaction between diabetes and AG for these two variables. The E(max) and Q(max) were reduced in rats with type 2 diabetes, but showed a significant rise after administration of AG to these diabetic rats. Moreover, the increase in Q(max) corresponded to a decrease in total peripheral resistance of the systemic circulation when the STZ and NA-induced diabetic rats were treated with AG. CONCLUSIONS AND IMPLICATIONS: AG therapy prevented not only the contractile dysfunction of the heart, but also the augmentation in LV internal resistance in rats with STZ and NA-induced type 2 diabetes.
Immunology. 2008 Jul;124(3):428-35.
Kim HA, Kim SH, Ko HM, Choi JH, Kim KJ, Oh SH, Cho KO, Choi IW, Im SY.
Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, Korea.
Nitric oxide plays a key role in the platelet-activating factor-induced enhancement of resistance against systemic candidiasis.
A study was conducted recently to find out the efficacy of Nitric oxide. The study reported that nitric oxide has the capability to play a major role in the platelet-activating factor-induced enhancement of resistance against systemic candidiasis.
Platelet-activating factor (PAF) has been demonstrated to augment resistance against Candida albicans infection. In this study, the role of nitric oxide (NO) in PAF-induced resistance in the kidneys was investigated. Pretreatment of the C. albicans-infected mice with PAF resulted in strong expression of messenger RNA (mRNA) and the protein synthesis of inducible nitric oxide synthase (iNOS). These PAF effects were inhibited to a significant degree by pretreatment with the nuclear factor-kappaB inhibitor, pyrrolidinedithiocarbamate. Pretreatment with PAF protected the mice from death caused by C. albicans infection and reduced the growth of fungus in the kidneys. The protective activity of PAF was abrogated by pretreatment with the iNOS inhibitor, aminoguanidine, and in the iNOS(-/-) mice. The PAF markedly increased the infiltration of neutrophils, but not macrophages, and also enhanced the mRNA expression levels of the CXC chemokine, keratinocyte-derived chemokine, in C. albicans-infected kidneys. These effects of PAF were attenuated in the aminoguanidine-treated mice and the iNOS(-/-) mice. These data show that NO plays an important role in PAF-induced protection against C. albicans.
Am J Primatol. 2008 Aug;70(8):796-802.
Brooks BA, Heffernan S, Thomson S, McLennan SV, Twigg SM, Yue DK.
Diabetes Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
The effects of diabetes and aminoguanidine treatment on endothelial function in a primate model of type 1 diabetes.
A review study was conducted recently to find our the efficacy of diabetes and aminoguanidine treatment on endothelial function. The study was conducted in a primate model of type 1 diabetes. The study reported that the effects of aminoguanidine on NO synthase might contribute to this phenomenon.
Abnormalities of endothelial function have been demonstrated in diabetes and are thought to play a role in the pathogenesis of diabetic complications. The aims of this study were to determine whether aminoguanidine, an inhibitor of glycation, can prevent endothelial and microcirculation abnormalities in a primate model of type 1 diabetes. Male baboons (Papio hamadryas) were assigned to one of the four groups: control, diabetes, control treated with aminoguanidine or diabetes treated with aminoguanidine. Diabetes was induced by streptozocin (60 mg/kg) and treated with once daily injection of insulin. Aminoguanidine was given subcutaneously (10 mg/kg), once a day. Diabetic animals had a mean duration of diabetes of 8.9 +/- 3.4 years and HbA1c of 8.9 +/- 1.1%. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in skin blood flow (SkBF) following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in SkBF in response to the nitric oxide (NO) donor sodium nitroprusside (SNP). Multiple regression analysis identified diabetes (P = 0.049) and aminioguanidine treatment (P = 0.026) as significant determinants of ACh response. The diabetic baboons treated with aminoguanidine had less Ach-mediated SkBF response compared with controls (1.39 +/- 0.32 vs. 2.26 +/- 0.61, F = 3.3, P = 0.04), but there was no difference between groups in SkBF response to SNP. We conclude that endothelial dysfunction can be demonstrated in this primate model of type 1 diabetes at a stage when overt diabetic complications are not present. This occurred in the absence of insulin resistance or significant hypercholesterolemia. Administration of aminoguanidine from the onset of diabetes was not able to prevent this abnormality and in fact aggravated the endothelial response. Effects of aminoguanidine on NO synthase may contribute to this phenomenon.
Bratisl Lek Listy. 2008;109(5):191-7.
Strapkova A, Antosova M, Nosalova G.
Department of Pharmacology, Comenius University, Jessenius Faculty of Medicine, Martin, Slovakia.
Effect of NO-synthase and arginase inhibition in airway hyperreactivity.
A study to evaluate the efficacy of NO-synthase and arginase inhibition in airway hyperreactivity. The study reported that NO-synthase isoforms and arginase are involved in the production of NO and in the control of bronchomotoric tonus.
BACKGROUND: The decreased L-arginine bioavailability, the basic substrate for nitric oxide synthesis, can be one of the factors contributing to the airways hyperreactivity. OBJECTIVES: We investigated the effect of various inhibitors of the enzyme activities utilizing L-arginine in a guinea pig model of experimental ovalbumin-induced airway hyperreactivity. METHODS: We used the in vivo pre-treatment with non-specific inhibitor of NO synthase No-nitro-L-arginine metylester (L-NAME) and relatively specific inhibitor of inducible NO synthase--aminoguanidine. Inhibitors were administered in one-shot (on the 14th day, 30 minutes before the inhalation of ovalbumin) or in a long-time regime (during the whole period of sensibilization by ovalbumin--14 days). We administered the inhibitor of arginase Nomega-hydroxy-L-arginine (NOHA) to the tracheal and lung tissue smooth muscle strips from sensibilized animals. RESULTS: We observed an increase in the tracheal smooth muscle response to histamine in animals that received an inhalation dose of L-NAME (40 mg/kg b.w.) or aminoguanidine (50 mg/kg b.w.) 30 minutes before the inhalation of ovalbumin but did not evoke any significant difference in the reactivity of lung tissue smooth muscle. Tracheal smooth muscle responded with enhanced contraction amplitude to histamine after chronic pre-treatment with L-NAME or aminoguanidine. The inhibition of arginase with NOHA in vitro decreased the tracheal and lung tissue smooth muscle reactivity to histamine. CONCLUSION: The results suggest that NO-synthase isoforms as well as arginase are involved in the production of NO and in the control of bronchomotoric tonus (Fig. 4, Tab. 2, Ref. 31).
Cornea. 2008 Aug;27(7):795-801.
Gül M, Emre S, Eşrefoğlu M, Vard N.
Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey.
Protective effects of melatonin and aminoguanidine on the cornea in streptozotocin-induced diabetic rats.
A review to find out the protective effects of melatonin and aminoguanidine on the cornea in rats with streptozotocin induced diabetes. The use of melatonin and aminoguanidine for a long term reduce the corneal injury in an STZ-induced diabetic rat model.
PURPOSE: This study was designed to investigate the protective effect of aminoguanidine (AG) and melatonin (M) on the cornea in a streptozotocin-induced diabetic rat model. METHODS: Twenty-eight Sprague-Dawley rats were used in this study. Animals were divided into 4 groups: control (C), diabetes (D), diabetes + AG (D+AG), and diabetes + M (D+M). Diabetes was induced by 1 intraperitoneal dose of 45 mg/kg of streptozotocin (STZ). In the treatment groups, the D + AG group received AG in their water (1 g/L), and D + M rats were injected with M (10 mg/kg/d) intraperitoneally. One of the groups remained an untreated diabetic group (D group). All animals were euthanized at the end of 8 weeks. After enucleation, eyes were fixed in 10% phosphate-buffered formalin and embedded in paraffin wax. Histochemical stains were applied, and specimens were examined under a light microscope. RESULTS: After 8 weeks, the rats in the diabetes group had significantly lower body weight and significantly higher blood glucose levels than those of the control, D + AG, and D + M groups. Diabetes resulted in prominent edema in the stroma with interruptions in the subepithelial basement membrane. These alterations were not prominent or were absent in the D + AG and D + M groups. The mean thicknesses of the cornea, corneal epithelium, and stroma were statistically significantly different between the C and D, and D and D + AG and D + M groups (P < 0.05). CONCLUSIONS: Long-term administration of AG and M reduced corneal injury in an STZ-induced diabetic rat model. AG and M may be potential candidates in the treatment of diabetic keratopathies. However, further studies are needed to elucidate the mechanisms of the protective effect of both molecules on diabetic corneal complications.
Biol Pharm Bull. 2008 Aug;31(8):1626-30.
Lee EH, Song DG, Lee JY, Pan CH, Um BH, Jung SH.
Natural Products Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung, Korea.
Inhibitory effect of the compounds isolated from Rhus verniciflua on aldose reductase and advanced glycation endproducts.
A research to find out the inhibitory effect of the compounds isolated from Rhus verniciflua. The main motto of this study was to evaluate the active principles for diabetic complications from Rhus verniciflua.
The aim of this paper was to evaluate active principles for diabetic complications from Rhus verniciflua. Nine compounds were isolated via bioactivity guided fractionation and isolation and tested for their effects on recombinant human aldose reductase and advanced glycation endproducts. Butein and sulfuretin isolated from ethyl acetate fraction were found to possess strongly both forms of aldose reductase and advanced glycation endproducts inhibition. The inhibitory activity of butein against a recombinant human aldose reductase (IC(50) value: 0.5 microM) was 2.6 times more potent that of epalrestat as a positive control (IC(50) value: 1.3 microM). The inhibitory potency of sulfuretin (IC(50) value: 124.7 microM) on advanced glycation end-products was about 10 times more potent that of aminoguanidine as a positive control (IC(50) value: 1231.0 microM). These compounds all displayed antioxidative activity which was measured by Photochem apparatus. It was concluded, therefore, butein and sulfuretin have antioxidative as well as aldose reductase and advanced glycation endproducts inhibitory effects. As a result, these compounds could be proposed as a leading compound for further study as a new natural products drug that could be used for diabetic complications.
Exp Toxicol Pathol. 2008 Aug 4.
Atasayar S, Gürer-Orhan H, Orhan H, Gürel B, Girgin G, Ozgüneş H.
Faculty of Pharmacy, Department of Toxicology, Hacettepe University, 06100 Sihhiye, Ankara, Turkey.
Preventive effect of aminoguanidine compared to vitamin E and C on cisplatin-induced nephrotoxicity in rats.
A comparison study between aminoguanidine and vitamin E and C. This study was conducted on rats with cisplatin-induced nephrotoxicity. The study reported that both vitamin C-E combination and aminoguanidine prevented the increase in serum urea levels.
In this study, the antioxidant effect of aminoguanidine on nephrotoxicity of a single dose of cisplatin is investigated and compared with the effects of well-known antioxidants vitamin C and E combination. Tubular damage and perivascular inflammation were observed in kidney samples of the cisplatin-administered groups. Aminoguanidine and vitamin C-E combination are found to be capable of preventing these effects of cisplatin. Liver tissues of all groups were intact. Cisplatin-induced oxidative stress was evidenced by significant decrease in glutathione and significant increase in malondialdehyde levels in kidney samples. Antioxidants with cisplatin decreased malondialdehyde levels. Antioxidants with cisplatin prevented the decrease in liver glutathione levels. The nephrotoxicity was confirmed biochemically by significant elevation of serum urea and creatinine levels. Both vitamin C-E combination and aminoguanidine prevented the increase in serum urea levels according to the cisplatin group.
Chest. 2008 Aug 21.
Brindicci C, Ito K, Torre O, Barnes PJ, Kharitonov SA.
Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on nitric oxide production and its metabolites in healthy controls, healthy smokers and COPD patients.
An evaluation on the efficacy of aminoguanidine on nitric oxide production and its metabolites in healthy controls, healthy smokers and COPD patients. Aminoguanidine is an inhibitor of inducible nitric oxide synthase. During the study the researchers administered a relatively selective aminoguanidine by nebulization in COPD patients, healthy smokers and healthy non-smoking subjects.
Background Nitric oxide (NO) is produced by resident and inflammatory cells in the respiratory tract by the enzyme NO synthase (NOS), which NOS exists in three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). NO production is increased in patients with COPD and the production of NO under oxidative stress conditions generates reactive nitrogen species that may amplify the inflammatory response in COPD. Methods To examine the role of increased NO in COPD, we administered a relatively selective iNOS inhibitor, aminoguanidine (AG), by nebulization in a double-blind, placebo-controlled study in COPD patients, healthy smokers and healthy non-smoking subjects. We investigated whether AG had any effect on exhaled NO produced in the central (J(NO)) and peripheral lungs (C(alv)), on NO metabolities (nitrite/nitrate, peroxinitrite, nitrotyrosine) and on a marker of oxidative stress (8-isoprostane) in exhaled breath condensate (EBC) and in sputum. Results AG administration resulted in a significant reduction in J(NO) compared with administration of the saline solution control in healthy subjects, smokers and COPD patients. C(alv) in smokers and in COPD patients was not completely inhibited one hour after AG inhalation, in marked contrast to previous results in asthma. Moreover, peroxynitrite, nitrite/nitrate levels were also increased in EBC and in sputum of smokers and COPD and were not completely inhibited following AG inhalation. 8-isoprostane levels were also increased in smokers and in COPD patients but were not reduced after AG inhalation. Conclusions These results suggest that cNOS isoform as well as iNOS might be involved in NO release and contribute to the high C(alv) and peroxynitrite production in COPD.
Aminoguanidine description...
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Drug category:Geroprotector
 Aminoguanidine scientific update
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