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.
"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). "
[Show abstract][Hide abstract] 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.
Neurotoxicity Research 05/2014; 26(4). DOI:10.1007/s12640-014-9475-y · 3.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.
Archives of Toxicology 08/2010; 84(11):825-89. DOI:10.1007/s00204-010-0577-x · 5.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the effects of Nacetyl cysteine (NAC) on the levels of reactive oxygen species in sepsis.
In this study, 30 Sprague-Dawley female rats weighing 180- 200 g were used. Rats were randomized into three groups, each containing 10 rats, as follows: Group I: Sham, Group II: Sepsis and Group III: Sepsis+NAC. Group I underwent only laparotomy. In Groups II and III, sepsis was induced by cecal ligation and perforation (CLP) technique. NAC (20 mg/kg/ day) was administered orally to Group III at 0, 8 and 16 hours. At the 24th hour, tissue and blood samples were taken for erythrocyte glutathione (GSH) and serum tumor necrosis factor (TNF)-? levels, histopathological determination, and lung, liver and kidney tissue malondialdehyde (MDA) analyses.
Group III was significantly different from the other groups with respect to erythrocyte glutathione, serum TNF-? and kidney MDA levels (p<0.05). There was no significant difference between the groups regarding liver MDA levels and histopathological parameters for lung, liver and kidney (p>0.05).
NAC treatment had beneficial effects on erythrocyte GSH, serum TNF-?, lung function, and kidney MDA levels in sepsis-induced rats. However, this beneficial effect was not confirmed as histopathological improvement. Further research is needed to prove the effect of NAC in sepsis treatment.
Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery: TJTES 07/2011; 17(4):293-7. DOI:10.5505/tjtes.2011.66743 · 0.38 Impact Factor
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