RESUMO
Although iron is a first-line pro-oxidant that modulates clinical manifestations of various systemic diseases, including diabetes, the individual tissue damage generated by active oxidant insults has not been demonstrated in current animal models of diabetes. We tested the hypothesis that oxidative stress is involved in the severity of the tissues injury when iron supplementation is administered in a model of type 1 diabetes. Streptozotocin (Stz)-induced diabetic and non-diabetic Fischer rats were maintained with or without a treatment consisting of iron dextran ip at 0.1 mL day(-1) doses administered for 4 days at intervals of 5 days. After 3 weeks, an extensive increase (p < 0.001) in the production of reactive oxygen species (ROS) in neutrophils of the diabetic animals on iron overload was observed. Histological analysis revealed that this treatment also resulted in higher (p < 0.05) tissue iron deposits, a higher (p < 0.001) number of inflammatory cells in the pancreas, and apparent cardiac fibrosis, as shown by an increase (p < 0.05) in type III collagen levels, which result in dysfunctional myocardial. Carbonyl protein modification, a marker of oxidative stress, was consistently higher (p < 0.01) in the tissues of the iron-treated rats with diabetes. Moreover, a significant positive correlation was found between ROS production and iron pancreas stores (r = 0.42, p < 0.04), iron heart stores (r = 0.54, p < 0.04), and change of the carbonyl protein content in pancreas (r = 0.49, p < 0.009), and heart (r = 0.48, p < 0.02). A negative correlation was still found between ROS production and total glutathione content in pancreas (r = -0.50, p < 0.03) and heart (r = -0.45, p < 0.04). In conclusion, our results suggest that amplified toxicity in pancreatic and cardiac tissues in rats with diabetes on iron overload might be attributed to increased oxidative stress.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Complexo Ferro-Dextran/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/induzido quimicamente , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Complexo Ferro-Dextran/administração & dosagem , Complexo Ferro-Dextran/farmacocinética , Masculino , Ratos , Ratos Endogâmicos F344 , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina , Distribuição TecidualRESUMO
The physicochemical characteristics of intravenous iron complexes affect the extent of weakly-bound iron and thus the degree of oxidative stress. The new preparation iron isomaltoside 1000 (IIM) was compared to iron sucrose (IS) and a control group in terms of biochemistry, oxidative stress, inflammatory markers and iron deposition in the liver, heart and kidneys of healthy rats. Renal function was significantly impaired in the IIM group versus both IS and controls. Liver enzymes were also significantly higher in IIM-treated animals versus the other groups, indicative of hepatic injury. Systolic blood pressure was significantly lower following IIM administration compared to IS or control animals. Oxidative stress in the liver, heart and kidneys was greater in the IIM group, as indicated by significantly increased levels of malondialdehyde and antioxidant enzyme activity, accompaniedby a significantly lower ratio of reduced to oxidized glutathione. Microscopy demonstrated more extensive positive staining for iron, and a smaller area of ferritin staining, in the liver, heart and kidneys of rats treated with IIM versus IS.Levels of the inflammatory markers TNF-alpha and IL6 were both significantly higher in the IIM group versus IS in all assessed tissues. These findings indicate that IIM has a less favorable safety profile than IS in healthy rats, adversely affecting iron deposition, oxidative stress and inflammatory responses, with impaired liver and renal function.
Assuntos
Dissacarídeos/toxicidade , Compostos Férricos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Creatinina/sangue , Dissacarídeos/administração & dosagem , Dissacarídeos/farmacocinética , Compostos Férricos/administração & dosagem , Compostos Férricos/farmacocinética , Óxido de Ferro Sacarado , Ferritinas/sangue , Ácido Glucárico , Hemoglobinas/metabolismo , Imuno-Histoquímica , Inflamação/sangue , Inflamação/induzido quimicamente , Injeções Intravenosas , Ferro/sangue , Complexo Ferro-Dextran/toxicidade , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Peso Molecular , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malondialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.
Assuntos
Compostos Férricos/toxicidade , Hematínicos/toxicidade , Complexo Ferro-Dextran/toxicidade , Nanopartículas de Magnetita/toxicidade , Maltose/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/análise , Pressão Sanguínea/efeitos dos fármacos , Creatinina/metabolismo , Feminino , Compostos Férricos/administração & dosagem , Óxido de Ferro Sacarado , Óxido Ferroso-Férrico , Ácido Glucárico , Coração/efeitos dos fármacos , Hematínicos/administração & dosagem , Imuno-Histoquímica , Inflamação/induzido quimicamente , Injeções Intravenosas , Complexo Ferro-Dextran/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Nanopartículas de Magnetita/administração & dosagem , Masculino , Maltose/administração & dosagem , Maltose/toxicidade , Peso Molecular , Proteinúria/induzido quimicamente , Ratos , Ratos Sprague-DawleyRESUMO
Iron chloride injections into the rat SNc can cause chronic decreases in striatal dopamine (DA) levels. However, changes in striatal DA content after iron-dextran injection into rat SNc have not been completely elucidated. The aim of this work was to measure striatal DA concentrations after iron-dextran injection into the SNc. We divided 40 male Wistar rats into five groups, including control, saline injected then sacrificed 7 days or 30 days later, and iron-dextran injected then sacrificed 7 days or 30 days later. Striatal DA content was measured in control animals and in all animals sacrificed 7 days or 30 days after injection, and motor performance was assessed in iron-dextran and saline injected groups 30 days after injection. The striatal DA levels were determined using HPLC. There were significant (P < 0.05) decreases in DA concentrations in the striatum ipsilateral to the injection site in the iron-dextran treated rats compared to control and saline-injected rats. There were no significant differences in DA concentration between the sham-operated (i.e., saline-injected) and control rats. We also observed motor deficits in the iron-dextran injected rats. The striatal DA reduction observed after iron-dextran injection may be attributable to iron-induced oxidative injury in the SNc. Motor deficits, in turn, may be explained by subsequent disturbances in striatal and cortical dopaminergic neuromodulation.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Complexo Ferro-Dextran/toxicidade , Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Substância Negra/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Dopamina/fisiologia , Regulação para Baixo/fisiologia , Hematínicos/uso terapêutico , Hematínicos/toxicidade , Complexo Ferro-Dextran/uso terapêutico , Masculino , Atividade Motora/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , RatosRESUMO
One hypothesis for the etiology of cell damage arising from iron overload is that its excess selectively affects mitochondria. Here we tested the effects of acute iron overload on liver mitochondria isolated from rats subjected to a single dose of i.p. 500 mg/kg iron-dextran. The treatment increased the levels of iron in mitochondria (from 21 +/- 4 to 130 +/- 7 nmol/mg protein) and caused both lipid peroxidation and glutathione oxidation. The mitochondria of iron-treated rats showed lower respiratory control ratio in association with higher resting respiration. The mitochondrial uncoupling elicited by iron-treatment did not affect the phosphorylation efficiency or the ATP levels, suggesting that uncoupling is a mitochondrial protective mechanism against acute iron overload. Therefore, the reactive oxygen species (ROS)/H+ leak couple, functioning as a mitochondrial redox homeostatic mechanism could play a protective role in the acutely iron-loaded mitochondria.
Assuntos
Sobrecarga de Ferro/fisiopatologia , Complexo Ferro-Dextran/toxicidade , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Injeções Intraperitoneais , Sobrecarga de Ferro/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias Hepáticas/metabolismo , Oxirredução/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
The effect of acute iron overload was studied in rat testes 20 h after a single administration of iron-dextran (500 mg/kg body wt, ip). Total testes iron content was 6.1-fold higher in iron-treated rats compared to controls. The endogenous level of lipid peroxidation was evaluated as 2-thiobarbituric acid-reactive substances (TBARS). Testes iron concentration (0.12-2.67 mumol/g of tissue) was positively correlated (r = 0.86; P < 0.01) with testes TBARS (26.2-77.5 nmol/g tissue). Testes content of lipid-soluble antioxidants, alpha-tocopherol, ubiquinol-9, and ubiquinol-10, were inversely correlated with testes iron content. The steady-state level of 8-oxo-7,8-dihydro-2'-deoxyguanosine in testes DNA was 25% higher (P < 0.01) in iron-treated rats compared to controls (2.4 +/- 0.2 oxo8dG/10(5)dG). The content of protein carbonyl groups (1.45 +/- 0.13 nmol/mg protein) and the activity of glutamine synthase (1.32 +/- 0.07 units/mg protein) were similar for the iron-treated and control rats. Fe treatment did not affect superoxide dismutase, catalase, and glutathione peroxidase activities. The results indicate that acute iron overload causes iron accumulation in rat testes, which is associated with increased lipid and DNA oxidative damage and depletion of lipid-soluble antioxidants.