Effects of N-Acetylcysteine/Deferoxamine, Taurine and RC-3095 on Respiratory Chain Complexes and Creatine Kinase Activities in Rat Brain After Sepsis

Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
Neurochemical Research (Impact Factor: 2.59). 04/2010; 35(4):515-21. DOI: 10.1007/s11064-009-0089-3
Source: PubMed


The pathogenesis of sepsis is characterized by an overwhelming systemic inflammatory response that can lead to multiple organ failure. Considering that we have recently demonstrated that mitochondrial respiratory chain and creatine kinase (CK) are altered in the brain of rats after cecal ligation and perforation (CLP) and that a combination of N-acetylcysteine/deferoxamine (NAC/DFX), taurine and RC-3095 were shown to be an effective treatment of sepsis, we investigated whether the alterations of these enzymes may be reversed by these drugs. The results demonstrated that CLP inhibited complexes I and II, and that all the treatments were able to reverse this inhibition in all brain areas studied in the present work. On the other hand, complexes III and IV were not affected by sepsis neither by any of the treatments. An increase in CK activity in brain of rats 12 h after CLP was also verified; the administration of NAC/DFX and taurine reversed the increase in CK activity in hippocampus, cerebral cortex, cerebellum and striatum. On the other hand, RC-3095 significantly decreased CK activity, when compared to sham group in all brain areas studied. This is a preliminary study which showed beneficial effects of the treatments we proposed.

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    • "During sepsis, antioxidant defences are overwhelmed, and ROS cause cellular damage, contributing to brain dysfunction (Cassol et al. 2010). Trace elements and vitamins as antioxidants may be able to significantly decrease mortality and shorten mechanical ventilation days and are associated with a trend toward reduced infectious complications in critically ill patients (Manzanares et al. 2012). "
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    ABSTRACT: Studies have consistently reported the participation of oxidative stress, energetic metabolism impairment, and creatine kinase (CK) activity alterations in rat brain in early times in an animal model of sepsis and persist for up to 10 days. We have assessed the antioxidant effects of administration of Ebselen (Eb) e diphenyl diselenide (PhSe)2 two organoselenium compounds on brain oxidative stress, energetic metabolism, and CK activity 12, 24 h, and 10 days after sepsis by cecal ligation and perforation (CLP) in rats. Male Wistar rats underwent either sham operation or CLP and were treated with oral injection of Eb (50 mg/kg) or (PhSe)2 (50 mg/kg) or vehicle. 12, 24 h, and 10 days after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex, and cortex) were obtained and assayed for thiobarbituric acid reactive species and protein carbonyls formation, mitochondrial respiratory chain, and CK activity. We observed in the results a reduction of oxidative damage to lipids and proteins in the different cerebral structures studied and times with the administration of (PhSe)2; however, Eb seems to exert the same effect. Such changes are reflected in the assessment of mitochondrial respiratory chain complexes by reversing the decreased activity of the complex caused by the model of CLP and CK activity. Our data provide the first experimental demonstration that (PhSe)2 was able to reduce the brain dysfunction associated with CLP-induced sepsis in rats, by decreasing oxidative stress parameters mitochondrial dysfunction and CK activity in early times and in late time.
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    Preview · Article · Aug 2010 · Archives of Toxicology
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    ABSTRACT: This study was aimed to evaluate and compare the effect of chronic hypoxia and aging in the oxidative status of brain vessels and synaptosomes. For this purpose we isolated brain vessels and synaptosomes from 3- and 12-month-old rats subjected to chronic hypoxia (10% O₂ for 7 days) or normoxia (21% O₂). Several parameters were evaluated: mitochondrial aconitase activity, hydrogen peroxide (H₂O₂) and malondialdehyde (MDA) levels and enzymatic [superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione reductase (GR)] and non-enzymatic [glutathione (GSH), glutathione disulfide (GSSG) and vitamin E] antioxidant defences. Concerning brain vessels, we observed an age-dependent increase in MDA levels and SOD, catalase, GR and GPx activities. In vessels isolated from young animals, chronic hypoxia induced an increase in H₂O₂, GSSG and vitamin E levels and CuZnSOD and catalase activities and a decrease in GSH levels. In mature animals, hypoxia induced a decrease in GSH/GSSG ratio, vitamin E levels and mitochondrial aconitase, MnSOD and GR activities and an increase in H₂O₂ levels and CuZnSOD and catalase activities. Concerning synaptosomes we observed an age-dependent increase in MDA levels, CuZnSOD and GPx activities and a decrease in MnSOD activity. In synaptosomes from young animals, chronic hypoxia induced a decrease in mitochondrial aconitase activity and GSH levels and an increase in CuZnSOD activity and GSSG levels. In synaptosomes from mature animals, hypoxia induced a decrease in mitochondrial aconitase activity, GSH/GSSG ratio, GSH and vitamin E levels and an increase in GSSG levels. Our results show that chronic hypoxia promotes and potentiates age-dependent oxidative imbalance predisposing to neurodegeneration. Further, synaptosomes and brain vessels are differently affected by aging and chronic hypoxia supporting the idea of the existence of tissue-specific susceptibilities.
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