Exacerbation Of Oxidative Stress Research Articles

Do the physiological aging of the placenta and the changes in angiogenesis marker sFlt-1 and PlGF concentrations predispose patients to late-onset preeclampsia?

Objective: Aging of the placenta is associated with natural processes that impair its functions. The processes are related to both oxidative stress exacerbation and the occurrence of higher concentrations of disordered angiogenesis markers. Both these types of processes are known to play roles in the development of preeclampsia. We attempted to show that natural ageing of the placenta can be one of the cofactors contributing to the development of late-onset preeclampsia. Patients, materials and methods: 159 pregnant patients were divided into four groups: Two of preeclampsia patients and two of patients with physiological pregnancies, depending on the gestational age. For each group, disordered angiogenesis markers sFlt-1 and PlGF before and after 34 weeks of gestation and in particular stages of gestation were analyzed. Results: Lower PlGF and sFlt-1/PlGF ratio values were found in cases of late-onset preeclampsia. In physiological pregnancies, sFlt-1 values were observed to increase and PlGF values to decrease with gestational age. An association was shown to exist between disordered angiogenesis markers and gestational age both in preeclampsia and physiological pregnancies. Conclusions: (1) Analyses of disordered angiogenesis markers in early- and late-onset preeclampsia patients and patients with physiological pregnancies allow for a suggestion that natural “ageing of the placenta” and placental hypoperfusion lesions exacerbating with the advancing gestational age are some of the causes of late-onset preeclampsia. (2) Cases of early-onset preeclampsia are associated with more severe changes of disordered angiogenesis marker concentrations, which may be indicative of a more considerable impairment of placental perfusion in such patients. (3) In the course of the physiological pregnancy, there is a gradual increase in sFlt-1 and decrease in PlGF, which implies an elevated angiogenesis disorder that progresses with the gestational age.

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration.

Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase (ROCK), insulin-like growth factor-1 (IGF-1), tumor necrosis factor α (TNF)-α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors (TLRs). Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.

200 - Aggravation of Oxidative Stress after Thioredoxin Reductase Deficiency Interrupts Starvation-Induced Autophagy through Oxidative Modification of Lysosomal Cathepsins

Oxidative damage and aggregation of cellular proteins is a hallmark of neurodegenerative diseases. Autophagy induction as a means for degradation of protein aggregates in lysosomes is an important vital process in normal conditions, and its interruption has been linked to neuronal cell death in these diseases. The importance of redox status of the cell in induction of autophagy has been linked to oxidative modification of cysteine groups in key molecular proteins. The cellular redox milieu is regulated by the availability of reduced glutathione and Thioredoxin system and is important in fine tuning of many cellular function including the autophagy machinery. Amongst the intricate network of many autophagy related proteins (ATGs), only ATG4 has been identified as a potential target of Trx; we therefore aimed to further investigate the role of Trx system in regulation of autophagy process. Using pharmacological and RNA-editing technology we show that exacerbation of oxidative stress after Trx-reductase deficiency in a model of nutritional stress in neuroblastoma SH-SY5Y cells interferes with autophagy progression and promotes apoptosis. This was associated with decreased protein-degradation in lysosomes due to altered lysosomal acidification and accumulation of autophagosomes. Previous studies have shown the critical role of low levels of ROS for normal induction of autophagy. Our study provides novel evidence that aggravated oxidative stress affects the final stages of autophagy by inhibiting lysosome maturation by modification of cathepsin processing. This provides a novel mechanistic link between protein aggregation and conversion of autophagy to apoptosis in SH-SY5Y cells.

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress.

Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity.

Vitamin Supplementation as an Adjuvant Treatment for Alzheimer's Disease.

Alzheimer's Disease (AD) is a slowly progressing neurodegenerative disorder representing a major health concern worldwide. This disorder is characterised by progressive dementia and cognitive decline. The pathological hallmarks of AD include the presence of Aβ plaques and tau neurofibrils. Research has shown that oxidative stress represents a major risk factor associated with AD pathology. Accumulation of Aβ plaques and relative lack of antioxidant defence mechanisms, including cellular antioxidant enzymes and dietary antioxidants like vitamins, assist in the exacerbation of oxidative stress. Reactive Oxygen Species (ROS) produced as the result of oxidative stress, that increase structural and functional abnormalities in brain neurons, which then manifests as dementia and decline in cognition. Data from numerous epidemiological studies suggests that nutrition is one of the most important yet modifiable risk factors for AD. Since oxidative stress contributes a great deal in the development and progression of AD, anything that could attenuate oxidative stress would help in decreasing the prevalence and incidence of AD. There is increasing evidence that supports the use of different antioxidant as an adjuvant treatment for AD. Vitamins are one such antioxidant that can be used as an adjuvant in AD treatment. This paper will focus on the evidence, based on current literature, linking the use of vitamin supplementations as an adjuvant treatment for AD.

Abstract 11103: Increase of Oxidative Stress Precipitated by Selenium Deficiency Plays a Role in Cardiac Hypofunction in Uremic Cardiomyopathy

Introduction: Various trace elements are deficient in hemodialysis patients, but the relationship of such deficiencies with cardiac hypofunction is unclear. We examined the deficiencies of trace elements in the blood and hair of hemodialysis patients diagnosed with uremic cardiomyopathy and investigated cardiac hypofunction mechanism from myocardial tissue. Methods: Using blood samples, we measured 25 elements including Se, Mn, Cu, and Zn by high-resolution inductively coupled plasma (ICP) mass spectrometry and ICP emission spectral analysis. We also compared glutathione peroxidase (GSHPx) activation and radical formation potential between the uremic cardiomyopathy patient group (n = 22) and a control group with normal cardiac function (n = 30). Using myocardial tissue, we assessed the exacerbation of oxidative stress by 8-hydroxy-2-deoxyguanosine, 4-hydroxy-2-nonenal, and GSHPx staining and microcirculatory disorder by the perivascular fibrosis area ratio (PVFR). We also measured concentrations of elements in hair at the Super Photon ring-8 GeV (SPring-8) facility. Results: Compared with the control group patients, the uremic cardiomyopathy patients had lower selenium (99.7 ± 21.4 vs. 146 ± 23.3 ng/ml, p < 0.00001) and manganese concentrations (0.39 ± 0.15 vs. 0.60 ± 0.12 ng/ml, p < 0.001); they also showed decreased activation of GSHPx (121 ± 33 vs. 328 ± 44 μmol/min/L, p < 0.00001), an antioxidant enzyme involving selenium, with only selenium concentration correlating to left ventricular ejection fraction (p = 0.0009). Oxidative stress marker staining, radical formation potential in serum, and PVFR were all augmented in the uremic cardiomyopathic patients (p < 0.001). Conclusions: Selenium concentration decrease in the serum of hemodialysis patients may reflect a decrease in GSHPx activation, increasing oxidative stress, and precipitating a coronary microcirculatory disorder involved in the cardiac hypofunction seen in uremic cardiomyopathy.

Upregulation of sestrin-2 expression protects against endothelial toxicity of angiotensin II.

Sestrin-2 (SESN2) is involved in the cellular response to different stress conditions. However, the function of SESN2 in the cardiovascular system remains unknown. In the present study, we tested whether SESN2 has a beneficial effect on vascular endothelial damage induced by angiotensin II (AngII). Firstly, we found that AngII induces expression of SESN2 in human umbilical vein endothelial cells (HUVECs) in a time-dependent and dose-dependent manner. We also found that knockdown of SESN2 using small RNA interference promotes cellular toxicity of AngII, as well as a reduction in cell viability, exacerbation of oxidative stress, and stimulation of apoptosis. In addition, our results show that the c-Jun NH (2)-terminal kinase (JNK)/c-Jun pathway is activated by AngII. Inhibiting the activity of the JNK pathway abolishes the increase in SESN2 induced by AngII. Importantly, overexpression of c-Jun promotes luciferase activity of the SESN2 promoter. These findings suggest that the inductive effect of SESN2 is mediated by the JNK/c-Jun pathway. Our results indicate that the induction of SESN2 acts as a compensatory response to AngII for survival, implying that stimulating expression of SESN2 might be an effective pharmacological target for the treatment of AngII-associated cardiovascular diseases.

The Presence and Role of Iron in Mild Traumatic Brain Injury: An Imaging Perspective

Mild traumatic brain injury (mTBI), although often presenting without the gross structural abnormalities seen in more severe forms of brain trauma, can nonetheless result in lingering cognitive and behavioral problems along with subtle alterations in brain structure and function. Repeated injuries are associated with brain atrophy and dementia in the form of chronic traumatic encephalopathy (CTE). The mechanisms underlying these dysfunctions are poorly understood. There is a growing body of evidence that brain iron is abnormal after TBI, and brain iron has also been implicated in a host of neurodegenerative disorders. The purpose of this article is to review evidence about the function of iron in the pathophysiology of mTBI and the role that advanced imaging modalities can play in further elucidating said function. MRI techniques sensitive to field inhomogeneities provide supporting evidence for both deep gray matter non-heme iron accumulation as well as focal microhemorrhage resulting from mTBI. In addition, there is evidence that iron may contribute to pathology after mTBI through a number of mechanisms, including generation of reactive oxygen species (ROS), exacerbation of oxidative stress from other sources, and encouragement of tau phosphorylation and the formation of neurofibrillary tangles. Finally, recent animal studies suggest that iron may serve as a therapeutic target in mitigating the effects of mTBI. However, research on the presence and role of iron in mTBI and CTE is still relatively sparse, and further work is necessary to elucidate issues such as the sources of increased iron and the chain of secondary injury.

Mitochondrial dysfunctions and altered metals homeostasis: new weapons to counteract HCV-related oxidative stress.

The hepatitis C virus (HCV) infection produces several pathological effects in host organism through a wide number of molecular/metabolic pathways. Today it is worldwide accepted that oxidative stress actively participates in HCV pathology, even if the antioxidant therapies adopted until now were scarcely effective. HCV causes oxidative stress by a variety of processes, such as activation of prooxidant enzymes, weakening of antioxidant defenses, organelle damage, and metals unbalance. A focal point, in HCV-related oxidative stress onset, is the mitochondrial failure. These organelles, known to be the “power plants” of cells, have a central role in energy production, metabolism, and metals homeostasis, mainly copper and iron. Furthermore, mitochondria are direct viral targets, because many HCV proteins associate with them. They are the main intracellular free radicals producers and targets. Mitochondrial dysfunctions play a key role in the metal imbalance. This event, today overlooked, is involved in oxidative stress exacerbation and may play a role in HCV life cycle. In this review, we summarize the role of mitochondria and metals in HCV-related oxidative stress, highlighting the need to consider their deregulation in the HCV-related liver damage and in the antiviral management of patients.

The Role of Kupffer Cells in Carbon Tetrachloride Intoxication in Mice

Carbon tetrachloride (CCl(4))-induced acute hepatitis is assumed to involve two phases. The initial phase, initiated within 2 h after CCl(4) administration, involves the generation of reactive oxygen species. The second phase is assumed to start about 8 h subsequent to CCl(4) administration and involves the oxidant-induced activation of Kupffer cells, which release various pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We investigated the role of Kupffer cells during CCl(4) intoxication using Nucling-knockout mice (the KO group), in which the number of Kupffer cells is largely reduced. Plasma alanine transaminase and aspartate transaminase levels demonstrated that the liver necrosis during the second phase was significantly alleviated in the KO group compared with that in the wild-type mice (the WT group). Plasma TNF-α concentrations in the WT group significantly increased 24 h after CCl(4) intoxication, whereas those in the KO group did not significantly increase. Plasma IL-6 levels also significantly increased in the WT group 24 h after CCl(4) administration, but those in the KO group did not increase at any time point. These results indicated that excess reactions of Kupffer cells, once primed by oxidants, were involved in the exacerbation of oxidative stress and liver damage during the second phase of CCl(4) intoxication.

Albumine sérique et insuffisance cardiaque : données récentes sur un nouveau paradigme

Hypoalbuminemia is a common condition in patients with heart failure and is mainly related to the malnutrition-inflammation complex syndrome. Other causal factors can be involved, which include hemodilution, liver dysfunction, increased transcapillary escape rate, renal and enteral loss. Evidence is growing that hypoalbuminemia independently predicts incident heart failure in patients with end-stage renal disease and elderly patients, as well as mortality in patients with heart failure regardless of left ventricular ejection fraction and clinical presentation. Hypoalbuminemia induces a low plasma oncotic pressure, which facilitates pulmonary edema in patients without critical increase in pulmonary capillary hydrostatic pressures. Hypoalbuminemia may also contribute to the progression of heart failure by favoring myocardial edema, volume overload, diuretic resistance and exacerbation of oxidative stress and inflammation. If relevant, removal of subclinical excess of fluid and renutrition may be indicated in patients with heart failure and hypoalbuminemia. Additional research is warranted to determine the specific role of serum albumin in the pathophysiologic process of heart failure and the potential benefits of targeted therapeutic interventions.

Zinc Levels and Oxidative Stress in Ataxia-telangiectasia Patients

RATIONALE: Ataxia-Telangiectasia (AT) is a rare degenerative autosomal recessive disease caused by a mutation in the gene encoding ATM protein (11q22-23). These patients tend to present increased oxidative stress and also neurodegeneration and a predisposition to cancer . There aren't any studies evaluating the role of antioxidant nutrients as zinc in the exacerbation of oxidative stress.

Heightened Sulfur Amino Acid Oxidation in Plasma and Erythrocytes in β-Thalassemia Major.

Abstract 4065Poster Board III-1000 BackgroundOxidative stress in β-thalassemia major is a well documented problem thought in part to be due to transfusional iron overload. Sulfur amino acid (SAA)-derived metabolites, chiefly glutathione (GSH), are critical components of cellular antioxidant defense. Inability to adequately regulate endogenous antioxidant status may lead to further exacerbation of oxidative stress. To characterize whether alteration in SAA metabolism contributes to heightened oxidative stress in thalassemia, we utilized a novel liquid chromatography linked electrospray positive tandem mass spectrometric (LC-MS/MS) technique to simultaneously quantify the redox states of cysteine (Cys) and GSH as well as the concentrations of major amino acid-derived metabolites in plasma and erythrocytes. MethodsAfter institutional review board approval, adult and pediatric subjects with β-thalassemia major were recruited for fasting blood samples drawn immediately prior to the next scheduled blood transfusion. Plasma and red blood cell samples were analyzed using the LC-MS/MS technique (J Chromatogr B 2009;in press) and compared with healthy controls. ResultsTwelve subjects with β-thalassemia major were recruited. The median age of the group was 26.5 years (range 11-41). The median liver iron concentration (LIC) determined by ferritometer was 11.9 mg/g dry-wt (range 1.0-34.8). The median ferritin level for the group was 1980 ng/mL (379-4730). Evidence of myocardial iron overload (T2* <20 msec) was present in 5 of 11 subjects. Plasma SAA redox analysis in these subjects showed significant oxidation of Cys and GSH. Total Cys redox status (Cysteine/2*Cystine ratios) decreased from 0.1 ± 0.01 in healthy controls to 0.08 ± 0.02 in thalassemia (p=0.02). Similarly, the plasma GSH redox state (GSH/2*GSSG ratio) decreased from 38.9 ± 13.7 in healthy controls to 6.7 ± 5.3 in thalassemia subjects (p=0.005). The total GSH and total Cys pools in the plasma did not differ between the two groups. Mirroring the patterns observed in the plasma compartment, the proportion of erythrocyte GSSG was also significantly elevated in thalassemia (0.65% vs. 0.04%, p=0.009), without a concomitant decline in total erythrocyte GSH pool. A significant 3-fold elevation in plasma cystathionine and S-adenosylmethionine levels suggests that key SAA metabolic pathways to augment synthesis of GSH may be up-regulated in thalassemia. In addition to alterations in SAA metabolite profiles, the thalassemia group was >3-fold deficient in plasma valine, spermine and citrulline compared with controls. We found that within this small group, the level of iron overload measured by serum ferritin, liver iron concentration and cardiac MRI T2* showed no correlation with the amount of oxidative stress measured by glutathione redox. DiscussionAssessment of SAA redox states and metabolic pathways has the potential to be a novel important marker in β-thalassemia major. The alterations in both Cys and GSH redox states without concomitant decline in their total concentration suggests either a significant increased rate of SAA oxidation and/or a decline in the capacity for NADPH-dependent reduction of oxidized disulfides. The latter may be supported by the evidence of profound hypocitrullinemia in thalassemia, which has been noted in subjects with inherited mitochondrial disorders (Proc Nat Acad Sci U S A 2009;106:3941-5). Finally, we show that the oxidative environment in the plasma affects the transfused erythrocytes which acquire characteristics of abnormal thiol metabolites observed in the plasma compartment. The demonstration of significant oxidative stress even in subjects with low body iron burden suggests that currently acceptable LIC levels may not be optimal, or that other contributors to the pro-oxidant state should be sought in thalassemia. Disclosures:No relevant conflicts of interest to declare.

Circulating oxidized LDL: a biomarker and a pathogenic factor

Oxidized LDL (oxLDL) contributes to many atherogenic steps in the vascular wall, but the significance of oxLDL in circulating blood remains unclear. Recent progress in procedures for measuring both human and murine oxLDL has provided growing evidence of the importance of circulating oxLDL. Circulating oxLDL is elevated in patients with advanced atherosclerosis, such as coronary heart disease and ischemic stroke, and also reflects early atherosclerotic changes and metabolic disorders including diabetes and obesity. In-vitro exposure to oxLDL increased mononuclear cell nuclear factor-kappaB activity, suggesting a pathogenic role of circulating oxLDL in exacerbation of oxidative stress. In addition, adenoviral administration of secreted scavenger receptor-A1, which functions as a decoy, suppresses foam cell formation in LDL receptor-deficient mice via a blockade of modified LDL incorporation into macrophages. Furthermore, when lectin-like oxLDL receptor-1 was ectopically expressed in the liver, circulating oxLDL was reduced, resulting in complete prevention of atherosclerotic progression in apolipoprotein E-deficient mice. Thus, circulating oxLDL impacts atherogenic formation. The roles of circulating oxLDL in atherosclerotic pathogenesis are now attracting considerable attention. OxLDL removal from circulating blood is a promising therapeutic strategy against atherosclerosis.

Aging is Associated with Increased Susceptibility to Western Diet‐Induced Glucose Intolerance and Endothelial Dysfunction in Mice

Western diets (WD) are associated with impaired glucose tolerance (GT) and vascular endothelial dysfunction, but it is unknown if these deleterious effects are exacerbated in older age. To explore this, GT and endothelium dependent dilation (EDD) were measured in older (O: 29–34 mo) and young (Y: 4–7 mo) B6D2F1 mice (N= 4–5/group) fed WD (40% fat, 6–8 wk) or normal chow (NC). Body mass was greater in O (+3%) and Y (+6%) WD vs. NC (Y vs. O, ns). However, epididymal fat mass was ∼350% greater in O, but only 97% greater in Y (WD vs. NC, P&lt;0.01). The area under the curve for glucose during a GT test (GTAUC) was greater in O WD vs. NC (1.63±0.13 vs. 1.27±0.05 (X 104) mg*min/ml, P=0.02), but not in Y (WD: 1.23±0.04 vs. NC:1.22±0.05). EDD (maximal carotid artery dilation to acetylcholine) was lower in O WD vs. NC (66±6 vs. 80±3%, P=0.03) but not in Y (WD: 91±8 vs. NC: 98±2%, P=0.43). Nitrotyrosine abundance, a marker of oxidative stress, was greater in the aortas of O vs. Y NC (1.8±0.4 vs. 1.0±0.2 AUs, P=0.02), but was increased in WD vs. NC only in O (+45%, 4.0±0.4 AUs, P&lt;0.01). These preliminary observations suggest that aging is associated with impaired resistance to the potentially adverse effects of WD on glucose tolerance and vascular endothelial function in B6D2F1 mice, possibly via exacerbation of oxidative stress. This could contribute to the increased risk of cardiovascular diseases with aging. NIH AG015897, AG006537, AG013038, AG022241

Disulfiram Augments Oxidative Stress in Rat Brain following Bilateral Carotid Artery Occlusion

We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram (DSF). These results indicate that BCAL alone decreases GSH content and limits glutathione reductase (GR) activity, and these changes were enhanced by DSF pretreatment. Similar observations were recorded with DSF alone. GR activity (74.3 ± 4.0 µmol min^–1 mg^–1 tissue; p < 0.001) and GSH content (1.23 ± 0.06 µmol min^–1 g^–1 tissue; p < 0.001) was attenuated in rats subjected to synergistic effect of BCAL and DSF with a concomitant increase of GSSG (0.006 ± 0.006 µmol min^–1 g^–1 tissue; p < 0.001). Recovery of GSH/GSSG level and GR activity during reperfusion following 30 min BCAL was considerably delayed (96 h) in the BCAL and DSF group as compared to the recovery time of 24 h in the group subjected to BCAL-reperfusion alone. Perturbation of GSH/GSSG homeostasis as a result of BCAL was augmented by DSF. These findings clearly demonstrate central nervous system oxidative stress due to a BCAL-DSF synergistic effect. Based on the results obtained with this model, we conclude that DSF increases brain oxidative stress and this may be detrimental to alcoholics who might drink and develop an acetaldehyde-induced hypotension while taking DSF.

Disulfiram augments oxidative stress in rat brain following bilateral carotid artery occlusion.

We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram (DSF). These results indicate that BCAL alone decreases GSH content and limits glutathione reductase (GR) activity, and these changes were enhanced by DSF pretreatment. Similar observations were recorded with DSF alone. GR activity (74.3 +/- 4.0 micromol min(-1) mg(-1) tissue; p < 0.001) and GSH content (1.23 +/- 0.06 micromol min(-1) g(-1) tissue; p < 0.001) was attenuated in rats subjected to synergistic effect of BCAL and DSF with a concomitant increase of GSSG (0.006 +/- 0.006 micromol min(-1) g(-1) tissue; p < 0.001). Recovery of GSH/GSSG level and GR activity during reperfusion following 30 min BCAL was considerably delayed (96 h) in the BCAL and DSF group as compared to the recovery time of 24 h in the group subjected to BCAL-reperfusion alone. Perturbation of GSH/GSSG homeostasis as a result of BCAL was augmented by DSF. These findings clearly demonstrate central nervous system oxidative stress due to a BCAL-DSF synergistic effect. Based on the results obtained with this model, we conclude that DSF increases brain oxidative stress and this may be detrimental to alcoholics who might drink and develop an acetaldehyde-induced hypotension while taking DSF.