RESUMO
In order to improve the understanding of the toxicity of pentavalent antimony (Sb(V)), we investigated the acute effects of meglumine antimoniate (MA) on the oxidative stress in heart, liver, kidney, spleen and brain tissue of mice. Levels of lipoperoxidation and protein carbonylation were measured to evaluate the oxidative status, whereas superoxide dismutase/catalase activity and glutathione levels were recorded to examine the antioxidative status. We observed that MA caused significant protein carbonylation in the heart, spleen and brain tissue. Increased lipoperoxidation was found in the liver and brain tissue. An imbalance between superoxide dismutase and catalase activities could be observed in heart, liver, spleen and brain tissue. Our results suggest that MA causes oxidative stress in several vital organs of mice. This indicates that the production of highly reactive oxygen and nitrogen species induced by MA might be involved in some of its toxic adverse effects.
Assuntos
Antiprotozoários/farmacologia , Meglumina/farmacologia , Compostos Organometálicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antiprotozoários/efeitos adversos , Encéfalo/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Catalase/metabolismo , Glutationa/análise , Coração/efeitos dos fármacos , Rim/química , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Meglumina/efeitos adversos , Antimoniato de Meglumina , Camundongos , Miocárdio/química , Compostos Organometálicos/efeitos adversos , Carbonilação Proteica/efeitos dos fármacos , Baço/química , Baço/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
Tissue methylmalonic acid (MMA) accumulation is the biochemical hallmark of methylmalonic acidemia. The disease is clinically characterized by progressive neurological deterioration and kidney failure, whose pathophysiology is still unclear. In the present work we investigated the effects of acute MMA administration on various parameters of oxidative stress in cerebral cortex and kidney of young rats, as well as the influence of acute renal failure on MMA-elicited effects on these parameters. Acute renal failure was induced by gentamicin, an aminoglycoside antibiotic whose utilization over prolonged periods causes nephrotoxicity. The administration of gentamicin alone increased carbonyl content and inhibited superoxide dismutase (SOD) activity in cerebral cortex, as well as increased thiobarbituric acid-reactive substances (TBA-RS) and sulfhydryl levels and diminished glutathione peroxidase activity in kidney. On the other hand, MMA administration increased TBA-RS levels in cerebral cortex and decreased SOD activity in kidney. Furthermore, the simultaneous administration of MMA and gentamicin to the rats provoked an augment in TBA-RS levels and superoxide generation in cerebral cortex and in TBA-RS, carbonyl and sulfhydryl levels in kidney, while diminished SOD activity in both studied tissues. Finally, nitrate/nitrite content, reduced glutathione levels, 2',7'-dihydrodichlorofluorescein oxidation and catalase activity were not affected by this animal treatment in either tissue. In conclusion, our present data are in line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on oxidative stress parameters in brain and peripheral tissues.
Assuntos
Injúria Renal Aguda/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Córtex Cerebral/metabolismo , Rim/metabolismo , Estresse Oxidativo , Injúria Renal Aguda/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Animais , Catalase/metabolismo , Creatinina/sangue , Gentamicinas , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , Ácido Metilmalônico , Nitratos/metabolismo , Nitritos/metabolismo , Oxirredução , Carbonilação Proteica , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
OBJECTIVE: To assess the presence of pulmonary embolism and inflammation after polidocanol foam injection into the peripheral veins of rabbits. METHOD: The animals were treated with polidocanol foam (1 or 3 mg/kg) or vehicle. Early (15 minutes) and late (30 days) animals were evaluated by perfusional lung scintigraphy and histopathological examination. RESULTS: In the control group no alterations were found. After polidocanol foam injection it was observed that an important reduction of pulmonary perfusion in the early periods, was mainly in the left lung (P < 0.001), with consequent embolism in the histological evaluation. In late periods it was observed that the presence of thrombus was with fibrin in small veins, compatible with chronic thrombus and the presence of chronic pulmonary inflammation. CONCLUSIONS: The injection of polidocanol foam in experimental animals can induce venous embolism and chronic inflammatory infiltration.
Assuntos
Pulmão/irrigação sanguínea , Pulmão/patologia , Polietilenoglicóis/efeitos adversos , Embolia Pulmonar/induzido quimicamente , Embolia Pulmonar/patologia , Soluções Esclerosantes/efeitos adversos , Doença Aguda , Animais , Doença Crônica , Feminino , Masculino , Polidocanol , Polietilenoglicóis/farmacologia , Coelhos , Soluções Esclerosantes/farmacologia , Fatores de TempoRESUMO
Pneumococcal meningitis is a severe infectious illness of the central nervous system (CNS), with high rates of lethality and morbidity, being that the microorganism and the host's inflammatory response are responsible for cerebral complications. Moreover, the bloodbrain barrier (BBB) itself secretes cytokines and, because of the bipolar nature of the BBB, these substances can be secreted into either the CNS compartment or in the blood, so patients with acute bacterial meningitis frequently develop sepsis. Therefore, the aim of this study was to evaluate the cytokine/chemokine levels in different vessels and the BBB integrity after pneumococcal meningitis induction. Wistar rats were infected with Streptococcus pneumoniae, and the BBB integrity was investigated using Evan's blue dye. Also, blood from the carotid artery and jugular vein was collected in order to perform tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-60 and cytokine-induced neutrophil chemoattractant-1 (CINC-1) analyses by enzyme-linked immunosorbent assay (ELISA). CINC-1 levels were increased at 6 h in the arterial plasma and at 3 and 6 h in the jugular plasma. We observed BBB breakdown between 12 and 24 h in the hippocampus and at 12 and 18 h in the cortex after pneumococcal meningitis induction. The increase of CINC-1 occurred prior to the BBB breakdown. CINC-1 is a neutrophil chemoattractant and it may be related to early events in the pneumococcal meningitis pathophysiology.
Assuntos
Barreira Hematoencefálica/patologia , Quimiocina CXCL1/sangue , Meningite Pneumocócica/patologia , Animais , Análise Química do Sangue , Ensaio de Imunoadsorção Enzimática , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Coal mining and incineration of solid residues of health services (SRHS) generate several contaminants that are delivered into the environment, such as heavy metals and dioxins. These xenobiotics can lead to oxidative stress overgeneration in organisms and cause different kinds of pathologies, including cancer. In the present study the concentrations of heavy metals such as lead, copper, iron, manganese and zinc in the urine, as well as several enzymatic and non-enzymatic biomarkers of oxidative stress in the blood (contents of lipoperoxidation = TBARS, protein carbonyls = PC, protein thiols = PT, α-tocopherol = AT, reduced glutathione = GSH, and the activities of glutathione S-transferase = GST, glutathione reductase = GR, glutathione peroxidase = GPx, catalase = CAT and superoxide dismutase = SOD), in the blood of six different groups (n = 20 each) of subjects exposed to airborne contamination related to coal mining as well as incineration of solid residues of health services (SRHS) after vitamin E (800 mg/day) and vitamin C (500 mg/day) supplementation during 6 months, which were compared to the situation before the antioxidant intervention (Ávila et al., Ecotoxicology 18:1150-1157, 2009; Possamai et al., Ecotoxicology 18:1158-1164, 2009). Except for the decreased manganese contents, heavy metal concentrations were elevated in all groups exposed to both sources of airborne contamination when compared to controls. TBARS and PC concentrations, which were elevated before the antioxidant intervention decreased after the antioxidant supplementation. Similarly, the contents of PC, AT and GSH, which were decreased before the antioxidant intervention, reached values near those found in controls, GPx activity was reestablished in underground miners, and SOD, CAT and GST activities were reestablished in all groups. The results showed that the oxidative stress condition detected previously to the antioxidant supplementation in both directly and indirectly subjects exposed to the airborne contamination from coal dusts and SRHS incineration, was attenuated after the antioxidant intervention.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Antioxidantes/uso terapêutico , Minas de Carvão , Suplementos Nutricionais , Estresse Oxidativo , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Exposição Ambiental , Glutationa/sangue , Glutationa/toxicidade , Glutationa Redutase/sangue , Glutationa Redutase/toxicidade , Humanos , Incineração , Peroxidação de Lipídeos , Metais Pesados/toxicidade , Metais Pesados/urina , Carbonilação Proteica , Superóxido Dismutase/sangue , Superóxido Dismutase/toxicidade , Substâncias Reativas com Ácido Tiobarbitúrico/toxicidade , Vitamina E/administração & dosagem , Vitamina E/uso terapêutico , alfa-Tocoferol/sangue , alfa-Tocoferol/toxicidadeRESUMO
Neuropeptide S (NPS) and its receptor NPSR comprise a recently deorphaned G-protein-coupled receptor system. There is a body of evidence suggesting the involvement of NPS in wakefulness, anxiety, locomotor activity and oxidative stress damage. Considering that mood stabilizers block the stimulatory effect of psychostimulants in rodents, the present study aimed to investigate the effects of the pretreatment with lithium and valproate on the hyperlocomotion evoked by NPS. Another relevant action induced by lithium and valproate is the neuroprotection against oxidative stress. Thus, aiming to get further information about the mechanisms of action of NPS, herein we evaluated the effects of NPS, lithium and valproate, and the combination of them on oxidative stress damage. Behavioral studies revealed that the pretreatment with lithium (100 mg/kg, i.p.) and valproate (200 mg/kg, i.p.) prevented hyperlocomotion evoked by NPS 0.1 nmol. Importantly, the dose of valproate used in this study reduced mouse locomotion, although it did not reach the statistical significance. Biochemical analyses showed that lithium attenuated thiobarbituric reactive species (TBARS) formation in the striatum, cerebellum and hippocampus. NPS per se reduced TBARS levels only in the hippocampus. Valproate did not significantly affect TBARS levels in the brain. However, the combination of mood stabilizers and NPS blocked, instead of potentiate, the neuroprotective effects of each one. No relevant alterations were observed in carbonylated proteins after all treatments. Altogether, the present findings suggested that mainly the mood stabilizer lithium evoked antagonistic effects on the mediation of hyperlocomotion and protection against lipid peroxidation induced by NPS.
Assuntos
Antipsicóticos , Comportamento Animal/efeitos dos fármacos , Compostos de Lítio , Neuropeptídeos/metabolismo , Animais , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Humanos , Compostos de Lítio/metabolismo , Compostos de Lítio/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Receptores Acoplados a Proteínas G , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Ácido Valproico/metabolismo , Ácido Valproico/farmacologiaRESUMO
BACKGROUND: It seems that a balance between anti and pro-inflammatory responses must be kept to eliminate the pathogen without inducing inflammatory damage in the host. Thus we determined the relation between macrophage activation and the severity and clinical outcome in septic patients. MATERIAL AND METHODS: This was a prospective study at a tertiary general intensive care unit. Thirty-three patients admitted with sepsis, severe sepsis or septic shock were included. As a control group, healthy volunteers were included matched to septic patients by age and sex. Peritoneal rat macrophages were cultured with 2% serum from healthy volunteers or from septic patients for determination of phagocytic potential or the capacity to produce cytokines. RESULTS: TNF and IL1 secretion by macrophages activated with serum from sepsis and severe sepsis patients was higher than with serum from healthy controls. In addition, proinflammatory cytokines released in vitro from macrophages, but not determined directly in the serum from patients, were lower in non-survivor septic patients when compared to survivors. In contrast, IL-10 secretion by macrophages activated with serum from septic patients was higher in nonsurvivors. In the septic shock group we observed a diminution in the phagocytic index compared to sepsis and severe sepsis groups, and the phagocytic index was higher in sepsis survivors. CONCLUSIONS: Markers of antiinflammation are predominant in more severe types of sepsis suggesting that antiinflammation is related to mortality.
Assuntos
Ativação de Macrófagos , Índice de Gravidade de Doença , Choque Séptico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Citocinas/sangue , Citocinas/imunologia , Humanos , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/imunologia , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Fagocitose , Estudos Prospectivos , Ratos , Ratos Wistar , Choque Séptico/sangue , Choque Séptico/imunologia , Resultado do TratamentoRESUMO
Neuropeptide S (NPS) is a recently discovered peptide which induces hyperlocomotion, anxiolysis and wakefulness. This study aimed to compare behavioral and biochemical effects of NPS with amphetamine (AMPH), and diazepam (DZP). To this aim, the effects of NPS (0.01, 0.1 and 1 nmol, ICV), AMPH (2 mg/kg, IP) and DZP (1 mg/kg, IP) on locomotion and oxidative stress parameters were assessed in mouse brain structures. The administration of NPS and AMPH, but not DZP, increased locomotion compared to control. Biochemical analyses revealed that AMPH increased carbonylated proteins in striatum, but did not alter lipid peroxidation. DZP increased lipid peroxidation in the cortex and cerebellum, and increased protein carbonyl formation in the striatum. In contrast, NPS reduced carbonylated protein in the cerebellum and striatum, and also lipid peroxidation in the cortex. Additionally, the treatment with AMPH increased superoxide dismutase (SOD) activity in the striatum, while it did not affect catalase (CAT) activity. DZP did not alter SOD and CAT activity. NPS inhibited the increase of SOD activity in the cortex and cerebellum, but little influenced CAT activity. Altogether, this is the first evidence of a putative role of NPS in oxidative stress and brain injury.
Assuntos
Anfetamina/farmacologia , Química Encefálica/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Diazepam/farmacologia , Hipnóticos e Sedativos/farmacologia , Atividade Motora/efeitos dos fármacos , Neuropeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Catalase/metabolismo , Injeções Intraperitoneais , Injeções Intraventriculares , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Carbonilação Proteica/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: To determine the effects of RC-3095 in clinical and histopathologic parameters and inflammatory mediators on complete Freund's adjuvant-induced arthritis (CFA). METHODS: The arthritis was induced by injection of CFA into the left hind footpad. The animals were divided into control, vehicle injected control, placebo group (saline subcutaneously 50ml/kg, once daily for 8 days after modeling), treatment group (0.3mg/kg of RC-3095 subcutaneously, once daily for 8 days after induction). Clinical evaluation was accomplished daily, through scoring of the paw edema. The animals were sacrificed 15 days after induction for collection of hind foot joints for histology. We used a histological scoring system which was previously described, and interferon (INF)-gamma, interleukin (IL)-1beta, tumor necrosis factor (TNF), interleukin (IL)-6 and interleukin (IL)-10 were measured by ELISA. RESULTS: There was a significant inhibition of joint histological findings in the RC-3095 treated group, including synovial inflammatory infiltration and hyperplasia, cartilage and bone erosion. IFN-gamma, IL-1beta, TNF, IL-6 and IL-10 serum levels were significantly lower in the treated group. Paw swelling and subcutaneous inflammation, evaluated clinically, were not different between CFA-induced groups. CONCLUSIONS: RC-3095 was able to improve experimental arthritis, attenuate joint damage and decrease serum levels of IFN-gamma, IL-1beta, TNF, IL-6 and IL-10. These data indicate that interference with GRP pathway is a potential new strategy for the treatment of RA that needs further investigational studies.
Assuntos
Artrite Experimental/tratamento farmacológico , Bombesina/análogos & derivados , Fragmentos de Peptídeos/uso terapêutico , Receptores da Bombesina/antagonistas & inibidores , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Bombesina/uso terapêutico , Adjuvante de Freund/imunologia , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Placebos , Distribuição Aleatória , Ratos , Ratos Wistar , Tarso Animal/imunologia , Tarso Animal/patologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Sepsis and its complications are the leading causes of mortality in intensive care units, accounting for 10-50% of deaths. Intensive care unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration, and/or global loss of cognitive function. In the present study, we investigated behavioral alterations in sepsis-surviving rats. One hundred and ten male Wistar rats (3-4 months, 250-300 g) were submitted to cecal ligation and puncture (CLP), and 44 were submitted to sham operation. Forty-four rats (40%) survived after CLP, and all sham-operated animals survived and were used as control. Twenty animals of each group were used in the object recognition task (10 in short-term memory and 10 in long-term memory), 12 in the plus-maze test and 12 in the forced swimming test. Ten days after surgery, the animals were submitted individually to an object recognition task, plus-maze and forced swimming tests. A significant impairment of short- and long-term recognition memory was observed in the sepsis group (recognition index 0.75 vs 0.55 and 0.74 vs 0.51 for short- and long-term memory, respectively (P < 0.05). In the elevated plus-maze test no difference was observed between groups in any of the parameters assessed. In addition, sepsis survivors presented an increase in immobility time in the forced swimming test (180 vs 233 s, P < 0.05), suggesting the presence of depressive-like symptoms in these animals after recovery from sepsis. The present results demonstrated that rats surviving exposure to CLP, a classical sepsis model, presented recognition memory impairment and depressive-like symptoms but not anxiety-like behavior.