Long-term cognitive impairment in sepsis survivors.
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Animals↗
Biomedical subjects
Felipe Dal-Pizzol
Publications and source records attributed to Felipe Dal-Pizzol.
Recognition memory impairment and brain oxidative stress induced by postnatal iron administration.
Iron accumulation in the brain has been implicated in the pathogenesis of neurodegenerative disorders. It is known that iron catalyses the formation of highly reactive hydroxyl radicals. Recent studies have implicated oxidative damage in memory deficits in rats and humans. The purpose of the present study was to investigate the long-term effects of iron treatment in four different phases of the neonatal period on recognition memory in rats. Additionally, parameters of oxidative stress in cerebral regions related to memory formation were evaluated. Male Wistar rats received vehicle or 10.0 mg/kg of Fe2+ orally at postnatal days 5-7, 12-14, 19-21 or 30-32. Animals given iron at any phase of the neonatal period showed impairments in long-term retention of object recognition memory, although only the group given iron from postnatal days 12-14 showed a complete memory blockade. Iron treatment induced oxidative damage in the brain as assessed by the thiobarbituric acid reactive species assay. Moreover, iron administration increased superoxide production in submitochondrial particles, suggesting impaired mitochondrial function; and there was an increase in superoxide dismutase activity in brain regions susceptible to iron administration. The results show that iron load in the early stages of life induces cognitive impairment possibly by inducing oxidative damage in the brain. These findings are consistent with the view that oxidative stress may be related to the cognitive decline observed in normal ageing.
Animals↗
Haloperidol and clozapine, but not olanzapine, induces oxidative stress in rat brain.
Typical and atypical antipsychotic drugs have been shown to have different clinical and behavioral profiles. Haloperidol (HAL) is a typical neuroleptic that acts primarily as a D2 dopamine receptor antagonist. It has been proposed that reactive oxygen species play a causative role in neurotoxic effects induced by HAL. We evaluated oxidative damage in rat brain induced by chronic HAL, clozapine (CLO) or olanzapine (OLZ) administration. Adult male Wistar rats received daily injections of Hal (1.5mg/kg), CLO (25mg/kg) or OLZ (2.5, 5.0 or 10.0mg/kg). Control animals were given saline (SAL; NaCl 0.9%). Thiobarbituric acid reactive substances (TBARS) and protein carbonylation were measured in the hippocampus (HP), striatum (ST) and cortex (CX). TBARS was increased in the striatum after HAL treatment. In contrast, there was a decrease of TBARS levels induced by HAL, CLO and OLZ treatments in the cortex. Protein carbonyls after HAL and CLO treatment was increased in the hippocampus, compared to control. In hippocampus, OLZ did not show significant difference to control in both oxidative parameters. Our findings demonstrated that atypical antipsychotic CLO produced less oxidative damage than HAL and we did not find oxidative damage induced by OLZ.
Animals↗
No evidence for oxidative damage in the hippocampus after acute and chronic electroshock in rats.
Although several advances has occurred over the past 20 years concerning the use of electroconvulsive therapy (ECT), little progress has been made in the mechanisms underlying its therapeutic or adverse effects. Thus, this work was performed in order to determine the level of oxidative damage and antioxidant enzyme activities early and late after acute and chronic electroconvulsive shock (ECS). We demonstrated a decrease in lipid peroxidation in the hippocampus immediately after and up to 30 days after a single or multiple electroconvulsive shock. This was also true for protein carbonyls in the acute protocol. We demonstrated an increase in catalase (CAT) and superoxide dismutase (SOD) activities at different time points after single and multiple electroconvulsive shock. Our findings, for the first time, demonstrated that after electroconvulsive shock, there is an increase in antioxidant enzyme activities and we cannot demonstrate oxidative damage in the hippocampus.
Adaptation, Physiological↗
Lung oxidative response after acute coal dust exposure.
Coal dust exposure can induce an acute alveolar and interstitial inflammation that can lead to chronic pulmonary diseases. The objective of this study was to describe the acute and later effects of acute coal dust exposure in lung parenchyma and the involvement of reactive oxygen species in coal dust effects. Forty-eight male Wistar rats (200-250 mg) were separated into four groups: 48 h, 7 days, 30 days, and 60 days after coal dust instillation. Gross mineral coal dust (3 mg/0.5 mL saline) was administered directly in the lungs of the treatment group by intratracheal instillation. Control animals received only saline solution (0.5 mL). Lipid peroxidation was determined by the quantity of thiobarbituric acid-reactive species (TBARS), oxidative damage to protein was obtained by the determination of carbonyl groups, the total radical-trapping antioxidant parameter (TRAP) was estimated by luminol chemoluminescence emission, catalase activity was measured by the rate of decrease in hydrogen peroxide, and superoxide dismutase activity was assayed by the inhibition of adrenaline autooxidation. Histological evaluation of coal dust-treated rats demonstrated an inflammatory infiltration after 48 h of the exposure. Initially, this was a cellular infiltration suggestive of lymphocyte infiltration with lymphoid hyperplasia that remained until 7 days after induction. This initial response was followed by a chronic inflammatory infiltration characterized by aggregates of macrophages 30 days after induction. This inflammatory response tended to resolve 60 days after induction, being similar to that of control animals. During both the acute and chronic phases of lung inflammation we observed a decrease in the TRAP in the lung of coal dust-exposed animals compared to that in control animals. We also observed an activation of superoxide dismutase 60 days after coal dust exposition. TBARS were increased 60 days after coal dust exposure and protein carbonyl groups increased at all times after coal dust exposure (48 h, 7 days, 30 days, and 60 days). These data suggested a biphasic inflammatory response and the involvement of oxidative damage in coal dust-induced lung damage.
Animals↗
Haloperidol- and clozapine-induced oxidative stress in the rat brain.
Haloperidol (HAL) is a typical neuroleptic that acts primarily as a D2 dopamine receptor antagonist. It has been proposed that reactive oxygen species play a causative role in neurotoxic effects induced by HAL. Adult male Wistar rats received daily injections of HAL (1.5 mg/kg) or clozapine (CLO, 25 mg/kg), an atypical neuroleptic, for 28 days. Control animals were given saline (SAL; NaCl 0.9%). Oxidative parameters in the brain were measured in the striatum (ST), hippocampus (HP) and cortex (CX). Thiobarbituric acid (TBA) reactive substances (TBAR) levels were increased by HAL treatment in the ST and decreased in CX of both of the HAL- and CLO-treated rats. Protein carbonyls were significantly increased by both HAL and CLO in the HP. The nonenzymatic antioxidant potential was decreased in the HP, and superoxide production was significantly increased in the ST following treatment with HAL. CLO induced an increase in superoxide production in the HP. Neither HAL nor CLO affected catalase (CAT) and superoxide dismutase (SOD) activities. The findings suggest that HAL and CLO can induce oxidative damage to the ST and HP in rats.
Animals↗
Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis.
OBJECTIVE: Oxidative stress plays an important role in the development of multiple organ failure and septic shock. Here we have evaluated the effects of a combination of antioxidants (N-acetylcysteine plus deferoxamine) in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). DESIGN: Prospective, randomized, controlled experiment. SETTING: Animal basic science laboratory. SUBJECTS: Male Wistar rats, weighing 300-350 g. INTERVENTIONS: Rats subjected to CLP were treated with either N-acetylcysteine (20 mg/kg, 3 hrs, 6 hrs, 12 hrs, 18 hrs, and 24 hrs after CLP, subcutaneously) plus deferoxamine (20 mg/kg, 3 hrs and 24 hrs after CLP, subcutaneously) or vehicle with or without "basic support" (saline at 50 mL/kg immediately and 12 hrs after CLP plus ceftriaxone at 30 mg/kg and clindamycin 25 mg/kg every 6 hrs). MEASUREMENTS AND MAIN RESULTS: After 12 hrs, tissue myeloperoxidase (indicator of neutrophil infiltration), thiobarbituric acid reactive species (as a marker of oxidative stress), catalase and superoxide dismutase activities (antioxidant enzymes), and mitochondrial superoxide production (index of uncoupling of electron transfer chain) were measured in major organs involved in septic response. Rats treated with antioxidants had significantly lower myeloperoxidase activity and thiobarbituric acid reactive species formation in all organs studied. Mitochondrial superoxide production was significantly reduced by antioxidant treatment. Furthermore, antioxidants significantly improved the balance between catalase and superoxide dismutase activities. Survival in untreated septic rats was 10%. Survival increased to 40% with fluids and antibiotics. In rats treated only with N-acetylcysteine plus deferoxamine, survival was also significantly improved (47%) in a manner similar to basic support. Survival increased to 66% with basic support with N-acetylcysteine plus deferoxamine. CONCLUSIONS: Our data provide the first experimental demonstration that N-acetylcysteine plus deferoxamine reduces the consequences of septic shock induced by CLP in the rat, by decreasing oxidative stress and limiting neutrophil infiltration and mitochondrial dysfunction, thereby improving survival.
Acetylcysteine↗
Antioxidants and sepsis: can we find the ideal approach?
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Acetylcysteine↗
Alternative activated macrophage: a new key for systemic inflammatory response syndrome and sepsis treatment?
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Animals↗
Protective effect of N-acetylcysteine and deferoxamine on carbon tetrachloride-induced acute hepatic failure in rats.
OBJECTIVE: Carbon tetrachloride (CCl4) is a lipid-soluble potent hepatotoxic; thus, it widely is used as an animal model of severe hepatic failure. Treatment with antioxidants may modulate the toxic effects of CCl4 on liver, generally with drug administration before CCl4, which can restrict its use in the clinical setting. We here describe the effects of N-acetylcysteine, deferoxamine, or both in the treatment of CCl4-induced hepatic failure. DESIGN: Prospective, randomized, controlled experiment. SETTING: Animal basic science laboratory. SUBJECTS: Male Wistar rats, weighing 200-250 g. INTERVENTIONS: Rats exposed to CCl4 were treated with N-acetylcysteine and/or deferoxamine or vehicle. MEASUREMENTS AND MAIN RESULTS: N-acetylcysteine plus deferoxamine treatment significantly attenuated hepatic and central nervous system oxidative damage after acute hepatic failure induced by CCl4. In addition, the serum levels of alanine aminotransferase, total bilirubin, and prothrombin time in the N-acetylcysteine plus deferoxamine group were significantly lower than those in the N-acetylcysteine or deferoxamine and saline groups. After N-acetylcysteine plus deferoxamine treatment, hepatocellular necrosis and inflammatory infiltration induced by carbon tetrachloride were greatly decreased. Survival in untreated rats was 5%. Survival increased to 25% and 35%, respectively, with N-acetylcysteine and deferoxamine treatment. In rats treated with N-acetylcysteine plus deferoxamine, survival was 80%. CONCLUSIONS: Our data provide the first experimental demonstration that N-acetylcysteine plus deferoxamine reduces mortality rate, decreases oxidative stress, and limits inflammatory infiltration and hepatocyte necrosis induced by CCl4 in the rat.
Acetylcysteine↗
Retinol-induced mdr1 and mdr3 modulation in cultured rat Sertoli cells is attenuated by free radical scavengers.
The effects of retinol on modulation of mdr genes in Sertoli cells were investigated. The hypothesis that free radical scavengers may attenuate the effect of retinol was also tested. Sertoli cells isolated from 15-day-old Wistar rats were cultured for 48 h and then treated with retinol for 24 h with or without free radical scavengers (1 mM mannitol, 0.1 mM Trolox or superoxide dismutase [200 U/ml]). Expression of mdr1, mdr2 and mdr3 genes was monitored by RT-PCR. Mitochondrial superoxide production was used as an index of ROS production. Expression of mdr1 and mdr3 was inhibited by retinol treatment (7 microM, 24 h), while mdr2 was not detected in response to any of the treatments. We also observed that retinol supplementation (7 microM, 24 h) increased superoxide production. The observed inhibition of mdr genes was attenuated by all co-treatments, suggesting that retinol-induced ROS are required for inhibition of mdr1 and mdr3 expression. The results suggest that retinol may play an important role in the modulation of the mdr gene family in cultured rat Sertoli cells and that these effects appear to be mediated by ROS.
ATP Binding Cassette Transporter, Subfamily B↗
Oxidative damage in brains of mice treated with apomorphine and its oxidized derivative.
Increasing evidence suggests that some of the neurobiological and neurotoxic actions of apomorphine and other dopamine receptor agonists might be mediated by their oxidation derivatives. The aim of the present study was to evaluate the effects of apomorphine and its oxidation derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), on oxidative stress parameters and antioxidant enzyme activity. Adult male CF-1 mice were treated with a systemic injection of apomorphine (0.4, 4.0 or 40.0 mg/kg) or 8-OASQ (0.4, 4.0 or 40.0 mg/kg). Animals were sacrificed by decapitation 24 h after treatment, and the forebrains were collected for analysis of thiobarbituric acid reactive species, protein carbonyls, the total radical-trapping antioxidant parameter, catalase and superoxide dismutase. These treatments did not induce lipid peroxidation at any dose tested. In contrast, apomorphine induced an increase in protein carbonylation and a decrease in total radical-trapping antioxidant parameter at all doses tested. 8-OASQ induced an increase in protein carbonylation and a decrease in total radical-trapping antioxidant parameter only at the higher dose tested. All apomorphine doses tested induced an increase in catalase, but not superoxide dismutase activities. In contrast, 8-OASQ induced a dose-dependent increase in CAT activity. The results suggest that apomorphine and its oxidation product, 8-OASQ, induce differential effects on CNS oxidative parameters.
Animals↗
Genotoxicity, recombinogenicity and cellular preneoplasic transformation induced by vitamin A supplementation.
In spite of being one of the first vitamins to be discovered, the full range of biological activities of Vitamin A remains incomplete. A growing body of evidence has demonstrated an apparent enhancement of carcinogenesis, induced by dietary retinol. Since DNA damage is a well-recognized inducer of carcinogenesis, the aim of this study was to test the possible genotoxic effect of dietary retinol, using different types of bioassays. Retinol caused an increased recombinogenic activity in Drosophila melanogaster larvae as measured by the SMART test. In mammalian cell cultures, retinol supplementation-induced DNA double-strands breaks (DSB) and single-strands breaks (SSB), cell cycle progression and proliferative focus formation in terminal-differentiated rat Sertoli cells and increased DNA fragmentation in Chinese hamster lung fibroblasts (V79 cells), as measured by the comet assay. Altogether, our results suggest that retinol causes DNA damage and chromosomal rearrangements, which may disturbs key physiological processes and lead to cell cycle progression and preneoplasic transformation of terminal-differentiated mammalian cells.
Animals↗
Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation.
OBJECTIVE: This study assessed parameters of free radical damage to biomolecules, mitochondrial superoxide production, superoxide dismutase, and catalase activities and their relationship to sepsis mortality. DESIGN AND SETTING: Prospective animal study in a university laboratory for experimental. SUBJECTS: 140 male Wistar rats. INTERVENTIONS: The animals were randomly divided into three groups: sham-operated (n=20), cecal ligation and perforation resuscitated with normal saline (n=40), and cecal ligation and perforation with normal saline plus antibiotics (n=40). MEASUREMENTS AND RESULTS: Blood samples were collected from all animals 3, 12, and 24 h after CLP through a jugular catheter inserted before CLP. Rats were evaluated during 5 days after the intervention. Nonsurvivor animals were grouped according to the duration between sepsis induction and death, and oxidative parameters were compared to survivors and sham-operated. Lipid peroxidation, protein carbonyls, and superoxide dismutase were significantly increased in nonsurvivor septic rats and were predictive of mortality. We demonstrated that there is a different modulation of superoxide dismutase and catalase in nonsurvivors during the course of septic response. There was a marked increase in superoxide dismutase activity without a proportional increase in catalase activity in nonsurvivors. CONCLUSIONS: This is the first report of plasma superoxide dismutase as an earlier marker of mortality. Ours results might help to clarify an important aspect of oxidative response to sepsis, i.e., an increase in superoxide dismutase activity without a proportional increase in catalase activity
Animals↗
Plasma oxidative parameters and mortality in patients with severe burn injury.
OBJECTIVE: To determine xanthine oxidase and superoxide dismutase activities, lipid peroxidation, protein carbonylation, and total radical-trapping antioxidant parameter in survivors and nonsurvivors patients with severe burn injury. DESIGN AND SETTING: Prospective, comparative observational study in an intensive care unit, burn division, in a trauma hospital. PATIENTS: Twenty-five consecutive patients who met the established criteria for severe burn injury (total burn surface area of more than 30%). MEASUREMENTS AND RESULTS: Plasma thiobarbituric acid reactive species and protein carbonyls levels were significantly higher in nonsurvivors than in survivors at 0 and 6 h. Elevated xanthine oxidase activity at 0 h was associated with adverse outcome after burn injury. In contrast, plasma superoxide dismutase activity and total radical-trapping antioxidant parameter did not differ significantly between nonsurvivors and survivors at any time point. CONCLUSIONS: For the first time we demonstrate the value of oxidative parameters, namely thiobarbituric acid reactive species, protein carbonyls, and xanthine oxidase activity, in identifying burn patients with a poor prognosis. Whether these parameters are merely markers of clinical course, or whether they signal specific deleterious effects of oxidative stress during the burn injury remains to be elucidated.
Adult↗
Superoxide production during sepsis development.
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Animals↗
Modulation of oxidative stress in response to gamma-radiation in human glioma cell lines.
Radiation therapy is routinely used in the management of primary central nervous system malignancies. However, the efficacy of this therapeutic modality is limited by the occurrence of resistance. In the present study, we investigated whether modulation of oxidative stress might underlie glioma cell radioresistance. Superoxide dismutase activity in irradiated M059J cells was two-fold higher than that in untreated controls, but did not significantly change in U-87 and U-138 cells. This is accompanied by an increase in reactive oxygen species content and decreases in cells viability. Pharmacological or genetic modulation of oxidative stress could be associated with an enhancement in the susceptibility of tumor cells to radiation therapy.
Animals↗
Enhanced UV-mediated free radical generation; DNA and mitochondrial damage caused by retinol supplementation.
Retinoid supplementation has been therapeutically used against various human disorders. We and others have demonstrated that retinol treatment causes free radical generation and increased iron uptake, iron storage and oxidative damage, both in vitro and in vivo. Here, we investigate the possible synergistic effect of retinol on UV-mediated free radical generation, oxidative damage to biomolecules and decreased cellular viability in primary cultured mammalian cells. Retinol treatment (7 microM) resulted in a threefold increase in UV-mediated free radical generation and a 40%, increase in lipoperoxidation. DNA fragmentation and mitochondrial oxidative damage also increased significantly in retinol-supplemented UV-irradiated cultured cells as compared to UV-irradiated control cells, which were only treated with the solvent used to deliver the retinol (0.1% ethanol). All measurements were restored to control values when an iron chelator, 1,10-phenanthroline (100 microM), or an OH* scavenger, mannitol (1 mM), was co-administrated. Rather than protecting against free radical generation, retinol seems to enhance UV-mediated oxidative damage and decreases cellular viability in cultured cells. We suggest that retinol-enhanced iron uptake and storage and increased reactive oxygen species generated by the Fenton reaction may act synergistically with UV-irradiation in causing oxidative damage to cells.
Alkadienes↗