Oxidative stress and antioxidants in epilepsy

In the present study, erythrocyte membrane lipid peroxidation, the percentage hemolysis, erythrocyte enzymes superoxide dismutase (SOD), glutathione peroxidase (GP), glutathione reductase (GR), catalase, and plasma vitamin C, vitamin E, vitamin A and ceruloplasmin activities and concentrations were determined in 29 epileptic patients and 50 normal controls. Ten patients who were treated with phenobarbital and who did not get convulsions for 1 year were considered for followup. Lipid peroxidation and percentage hemolysis in patients with epilepsy was significantly higher when compared to controls. Moreover, plasma ceruloplasmin concentrations were also markedly increased in these cases. Erythrocyte GR and plasma vitamin C and A concentrations were significantly lower in epileptics when compared to controls. In the followup patients, the erythrocyte GR was significantly higher than their pre-treated condition. Furthermore, the plasma vitamin A, E and C concentrations have attained the normal range. This study indicates that the antioxidant status in blood of epileptic patients which was low compared to controls, improved after treatment, suggesting that free radicals may be implicated in epilepsy.     

Oxidative stress in pathogenesis of COPD

Cigarette smoke and aging are major risk factors of chronic obstructive pulmonary disease(COPD). It remains unsolved how long -term smoking with age affects the molecular responses in the lung. Respiratory tract is the major interface to the environment and is rich in glutathione, which protects lung from oxidative stress. We performed bronchoalveolar lavage for nonsmokers and smokers of various ages, who were further categorized according to the presence of emphysema on high-resolution computed tomography. We thus evaluated glutathione antioxidant system in BAL fluid. Characterization of older smokers with long-term smoking histories, contrasted with young recent smokers, may in part explain the predisposition of the lungs to destructive lung diseases. On the other hands, oxidative stress results from an imbalance in aerobic metabolism and poses a serious threat to cellular apoptosis, leading to emphysematous lung destruction. The therapeutic interference with targeted up-regulation of protective mechanisms might be critical for the success of future COPD therapies.     

Oxidative stress and endothelial dysfunction: therapeutic implications

In a previous issue of Annals of Medicine, we presented evidence in support of the concept that an abnormally increased production of reactive oxygen species plays a central role in the genesis and progression of cardiovascular disease. While a number of preclinical lines of evidence support this concept, and despite the results of many studies suggesting a beneficial impact of antioxidant drugs on endothelial function, large clinical trials have failed to demonstrate a benefit of antioxidants on cardiovascular outcomes. Studies exploring the possibility that classical antioxidants such as vitamin C, vitamin E, selenium, or folic acid may improve the prognosis of patients with cardiac disease have substantially reported neutral-and occasionally negative-results. In contrast, medications such as statins, ACE inhibitors, certain β-blockers, or angiotensin I receptor blockers, which possess indirect 'ancillary' antioxidant properties, have been associated with beneficial effects in both preclinical studies and large clinical trials. The reasons for the failure of the 'direct' approach to antioxidant therapy, and for the success of the therapy with these drugs, are discussed in the present review.     

Oxidative stress induced in pathologies: the role of antioxidants.

Exposure to oxidant molecules issued from the environment (pollution, radiation), nutrition, or pathologies can generate reactive oxygen species (ROS for example, H2O2, O2-, OH). These free radicals can alter DNA, proteins and/or membrane phospholipids. Depletion of intracellular antioxidants in acute oxidative stress or in various diseases increases intracellular ROS accumulation. This in turn is responsible for several chronic pathologies including cancer, neurodegenerative or cardiovascular pathologies. Thus, to prevent against cellular damages associated with oxidative stress it is important to balance the ratio of antioxidants to oxidants by supplementation or by cell induction of antioxidants.     

Oxidative stress in patients with COPD and pulmonary hypertension

OBJECTIVE: Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Oxidant/antioxidant imbalance has also been reported in various forms of pulmonary hypertension. The present study aimed to assess systemic oxidative stress, as reflected by serum malondialdehyde (MDA) concentrations and activities of antioxidant enzymes in erythrocytes [glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT)] in patients with and without pulmonary hypertension secondary to COPD. PATIENTS AND METHODS: Seventy-five patients (58 male) with COPD (mean age 65.1 +/- 1.2 years; mean smoking history 35.6 +/- 3.8 pack-years) were studied. Twenty-one healthy non-smokers served as a control group. Pulmonary function was evaluated with body plethysmography; mean and systolic pulmonary artery pressures (Ppa) were assessed with Doppler echocardiography. Serum concentrations of MDA and activities of GPX, SOD and CAT in washed red blood cells were measured using spectrophotometry. RESULTS: Pulmonary hypertension was present in 28 patients with COPD (systolic Ppa: 46.4 +/- 2.3 mmHg; mean Ppa: 26.0 +/- 1.9 mmHg) and absent in 47 (systolic Ppa: 22.9 +/- 0.8 mmHg; mean Ppa: 13.4 +/- 0.6 mmHg). Compared with the healthy control group, all the patients (with or without pulmonary hypertension) had higher serum MDA concentrations (1.5 +/- 0.1 versus 2.3 +/- 0.1 versus 2.3 +/- 0.1 nmol/mL, ANOVA, P < 0.001) and lower erythrocyte GPX activity (51.3 +/- 3.2 versus 42.2 +/- 2.0 versus 41.3 +/- 2.5 U/g Hb, P = 0.029), whereas SOD (1121.1 +/- 29.0 versus 1032.6 +/- 21.8 versus 1032.7 +/- 36.2 U/g Hb, P = 0.063) and CAT activities (4.9 +/- 0.2 versus 4.6 +/- 0.1 versus 4.7 +/- 0.2 U/g Hb; P= 0.454) were similar. No differences were observed in serum MDA concentrations or activities of GPX, SOD and CAT in erythrocytes between COPD patients with and without pulmonary hypertension. CONCLUSION: The study demonstrates the presence of oxidative/antioxidative imbalance in the systemic circulation in patients with COPD: compared with healthy subjects, COPD patients had higher serum MDA concentrations and lower GPX activity in erythrocytes. The magnitudes of the increase in MDA and reduction in GPX activity were similar in COPD patients with pulmonary hypertension and in those with normal pulmonary artery pressures.     

慢性阻塞性肺疾病患者氧化应激和病情变化的研究

目的 探讨慢性阻塞性肺疾病(COPD)患者急性加重期及病情缓解后氧化应激程度.方法 选取33例慢性阻塞性肺疾病急性加重期(AECOPD)患者(实验组)及31例健康体检者(对照组)采用菲罗啉比色法检测血浆总抗氧化能力(TAC)、硫代巴比妥酸比色法检测血浆丙二醛(MDA)含量、改良Hafeman直接测定法(DNTB)检测血浆谷胱甘肽过氧化物酶(GSH-PX)活力,同时进行动脉血气检测及功能性呼吸困难评分.结果 实验组病情缓解后动脉血氧分压(PaO2)(62.32±8.50)mmHg(1 mmHg=0.133 kPa)较急性加重期(49.06±7.64)mmHg升高(P＜0.01);动脉血二氧化碳分压(PaCO2)(41.81±7.23)mmHg较急性加重期(45.63±7.81)mmHg降低(P＜0.05).实验组病情缓解后功能性呼吸困难评分(MMRC)(1.55±0.61)较急性加重期(2.61±0.68)显著好转(P＜0.01).实验组病情缓解后血浆TAC,GSH-PX均较急性加重期明显升高(6.77±1.28)kU/L vs(5.52±1.15)kU/L、(168.17±43.66)kU/L vs(132.27±39.45)kU/L明显升高(P＜0.01),但显著低于对照组(7.76±1.41)kU/L、(197.92±53.28)kU/L(均P＜0.01).实验组病情缓解后血浆MDA(5.43±1.86)μmol/L较急性加重期(7.28±2.03)μmol/L明显降低(P＜0.01),但显著高于对照组(3.89±1.46)μmol/L(均P＜0.01).实验组急性加重期及病情缓解后血浆TAC均与MDA呈负相关(r=-0.587、r=-0.450,P＜0.01或＜0.05).实验组急性加重期及病情缓解后血浆TAC均与GSH-PX及PaO2呈正相关(r分别0.556、0.583和0.433、0.396,均P＜0.05或＜0.01).实验组急性加重期及病情缓解后血浆TAC与PaCO2无明显相关(r分别为0.230、-0.225,均P＞0.05);实验组急性加重期及病情缓解后血浆MDA与PaO2呈负相关(r分别为-0.463、-0.411,均P＜0.05)、与PaCO2无明显相关(r分别为0.198、-0.232,均P＞0.05).结论 AECOPD患者体内氧化/抗氧化失衡,存在氧化应激;AECOPD患者加重缓解后,氧化应激损伤明显减轻;AECOPD患者氧化损伤与缺氧密切相关.     

Oxidative stress in patients with asthma and its relation to uncontrolled asthma

This study aims to evaluate markers of oxidative stress in Tunisian asthmatic patients and investigate whether their markers are correlated with uncontrolled asthma.This prospective cohort study was conducted on 48 healthy subjects and 60 patients with asthma (34 patients with controlled asthma and 26 patients with uncontrolled asthma). The levels of malondialdehyde (MDA), advanced oxidation protein products (AOPP), and glutathione (GSH), as well as the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), were estimated in plasma by spectrophotometry.Asthmatic patients have significantly higher plasmatic levels of MDA and AOPP than healthy controls (p < 0.001). Lower GSH level and GPx activity were found in patients with asthma compared to controls (p < 0.001). In contrast, higher SOD activity was noted in asthmatic patients (p < 0.001).The comparison among the patients with controlled asthma and uncontrolled asthma revealed increased MDA and AOPP levels and SOD activity (p < 0.001) as well as a decreased GSH level and GPx activity (p = 0.004, p = 0.019) in patients with uncontrolled asthma. Spirometry level was significantly correlated with SOD activity (r = 0.447; p = 0.010), whereas no significant correlations were found with the other parameters (MDA, AOPP, GSH, and GPx).Asthmatic patients, especially those with uncontrolled asthma, suffer a high degree of reactive oxygen species (ROS) formation causing considerable oxidative stress. Increased MDA level and SOD activity and reduced GPx activity were predictors of poorly controlled asthma.     

氧化应激与阿尔茨海默病:病理学与治疗学综述

背景:在神经退行性疾病中,阿尔茨海默病的发病机制尚不十分清楚。目的:分析氧化应激与阿尔茨海默病的关系及其在治疗上的作用。设计:相关文献分析。地点和对象:综述若干相关杂志中氧化应激与阿尔茨海默病的发病的关系,及患者采用中医治疗后的效果。干预:①抗氧化剂。②中医中药治疗。主要观察指标:阿尔茨海默病病理过程中的氧化应激,中医药治疗阿尔茨海默病新方法。结果:近年的生物医学文献中探讨了氧化应激在阿尔茨海默病的致病过程中的作用以及相应的治疗对策,尤其是中医药在这一领域的研究成果颇多。结论:氧化应激是导致阿尔茨海默病的一种重要致病因素,抗氧化剂和一些有关的中药复方有望成为有效治疗阿尔茨海默病的药物。     

Oxidative stress and antioxidants in patients with cardiogenic shock complicating acute myocardial infarction

BACKGROUND: Lipid peroxidation and derived oxidized products are being intensively investigated because of their potential to cause injury and because of their pathogenic role in several diseases. The view that an excess of lipid peroxidation products is present and is relevant in the pathogenesis of cardiogenic shock-induced damage has still not received definitive support. METHODS: To evaluate the extent of lipid peroxidation, the status of enzymatic and nonenzymatic antioxidants in patients with cardiogenic shock that complicate acute myocardial infarction (AMI) and to compare with normal subjects. RESULTS: Compared with normal subjects, cardiogenic shock patients had higher malondialdehyde, conjugated dienes and reduced activities of erythrocyte antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and lower concentrations of reduced glutathione (GSH) in erythrocyte and in plasma GSH, vitamin C, vitamin E and in beta-carotene. CONCLUSIONS: Cardiogenic shock is associated with greater than normal lipid peroxidation and with an imbalance in antioxidants' status. These results indicate that low activities of SOD, CAT, GPx and low concentrations of GSH, vitamin C, vitamin E and beta-carotene in the circulation of patients with cardiogenic shock complicating AMI may be due to increased utilization to scavenge lipid peroxides. Decrease in plasma concentrations of GSH, vitamin E and beta-carotene seems to be responsible for the elevation of lipid peroxidation in cardiogenic shock complicating AMI compared with MI.     

Oxidative stress in neurodegenerative diseases: therapeutic implications for superoxide dismutase mimetics

Evidence of oxidative stress is apparent in both acute and chronic neurodegenerative diseases, such as stroke, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Increased generation of reactive oxygen species simply overwhelm endogenous antioxidant defences, leading to subsequent oxidative damage and cell death. Tissue culture and animal models have been developed to mimic some of the biochemical changes and neuropathology found in these diseases. In doing so, it has been experimentally demonstrated that oxidative stress plays a critical role in neuronal cell death. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) have demonstrated therapeutic efficacy in models of neurodegeneration. However, delivery and stability issues have reduced the enthusiasm to clinically develop these proteins. Most recently, SOD mimetics, small molecules which mimic the activity of endogenous superoxide dismutase, have come to the forefront of antioxidant therapeutics. This review will examine the experimental evidence supporting the use of scavengers of superoxide anions in treating some neurodegenerative diseases, such as stroke, PD and ALS, but also the pitfalls that have met antioxidant molecules in clinical trials.     

Oxidative stress and cardiovascular disease in type 2 diabetes: the role of antioxidants and pro-oxidants.

Oxidative stress occurs when there is an imbalance between free radical production and antioxidant capacity. This may be due to increased free radical formation in the body and/or loss of normal antioxidant defenses. Oxidative stress has been associated with the development of cardiovascular disease. The role of antioxidants in the primary and secondary prevention of coronary heart disease is currently under study. Although epidemiologic evidence indicates that antioxidants may decrease cardiovascular risk, clinical trial data are not conclusive. Information regarding the use and benefits of antioxidants in persons with diabetes is limited. Persons with diabetes may be more prone to oxidative stress because hyperglycemia depletes natural antioxidants and facilitates the production of free radicals. In addition, other factors such as homocysteine, insulin resistance, and aging may be contributory. This article highlights landmark clinical trials that have examined the cardioprotective effect of antioxidants. Because these trials have not been designed to study persons with diabetes, and clinical trial data for this group are not available, correlational studies are also presented. Finally, the concept of oxidative stress, the antioxidant and pro-oxidant factors that may contribute to oxidative stress, and the consequences of oxidative stress in persons with type 2 diabetes are presented. Key words: antioxidants, clinical trials,     

Complement inhibition as a therapeutic strategy in retinal disorders

Introduction: Dry age-related macular degeneration (AMD) and Stargardt Macular Dystrophy (STGD1) result in vision loss due to progressive atrophy of the macula and lack of effective treatments. Numerous studies have implicated complement-associated inflammation as a contributor to both diseases.

Areas covered: The complement factor D inhibitor, lampalizumab, failed to halt geographic atrophy (GA) progression in phase 3 studies. The complement factor 3 (C3) inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials. The intravenous complement factor 5 (C5) inhibitor, eculizumab, failed to halt GA progression in a phase 2 study. Another C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials. LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies. A phase 1 trial is evaluating the effects of combining LFG316 and CL561. Complement inhibition by gene therapy will be explored in the phase 1 trial of HMR59 in AMD patients.

Expert opinion: While complement inhibition has not yet demonstrated the ability to halt GA progression in a phase 3 trial, further study is warranted.     

Glucagon as a therapeutic agent in the treatment of asthma

Glucagon, an activator of cyclic AMP that produces smooth muscle relaxation, was studied to determine if it had the ability to reverse or modify the degree of bronchospasm in asthmatic patients. Fourteen patients with mild to moderately severe bronchospastic exacerbation of asthma were studied using peak expiratory flow rates (PEFR) before and after receiving one milligram of glucagon intravenously. Eight (57%) of the 14 patients demonstrated a mean PEFR increase of 113 L/min ten minutes following glucagon administration and were termed responders. This study suggests that further investigation of the role of glucagon in asthmatic patients is warranted.     

Oxidative injury and antioxidants in coronary artery bypass graft surgery: off-pump CABG significantly reduces oxidative stress

BACKGROUND: Coronary artery bypass grafting (CABG) can now be performed with or without cardiopulmonary bypass. The former entails global ischemia followed by reperfusion after declamping, whereas the latter does not. In view of growing evidence that reperfusion is associated with oxidative stress, we studied the extent of oxidative stress and antioxidant status in patients undergoing on-pump and off-pump CABG to determine whether the latter significantly reduces oxidative stress. METHODS: Thirty patients were initially enrolled for the study. The inclusion criteria included patients with atherosclerotic triple vessel disease, undergoing elective CABG, with good LV function, no major risk factors for surgery, with all biochemical investigations within normal limits, having stable angina and no history of previous infarct. Patients with valvular heart disease, ventricular aneurysm, heart failure and poor left ventricular function were excluded. These were alternately posted for on-pump and off-pump CABG. Eight patients were excluded as they developed unforeseen complications during the surgery. Out of the remaining 22 patients, 13 underwent off-pump CABG and 9 underwent on-pump CABG. Five blood samples were collected; baseline, 5, 15, 60 min and 24 h after reperfusion. Samples were analyzed for thiobarbituric acid reactive substances (TBARS), glutathione (G-SH) and catalase (CAT). The results were compared with their preanaesthetic levels in both the groups and also with 20 age- and sex-matched normal healthy individuals. RESULTS: Lipid peroxidation was significantly increased after reperfusion in patients undergoing on-pump CABG, maximum increase (p<0.0001) was seen 1 h after reperfusion, whereas off-pump CABG reduces oxidative stress. The G-SH levels were significantly decreased after reperfusion in on-pump and off-pump CABG patients, maximum decrease (p<0.0001) was seen 5 min after reperfusion in on-pump CABG. The catalase activity was significantly increased after reperfusion in on-pump and off-pump CABG patients, maximum increase (p<0.0001) was seen 1 h after reperfusion in on-pump CABG. CONCLUSION: Significant increase in oxidative stress was seen in patients undergoing on-pump CABG, whereas oxidative stress was less in off-pump CABG patients. The G-SH levels were decreased and Catalase activity was increased significantly in both on-pump and off-pump CABG patients.     

Oxidative stress as a novel target in pediatric sepsis management

Sepsis with secondary multisystem organ dysfunction syndrome is the leading cause of death in the pediatric intensive care unit. Increased reactive oxygen species may influence circulating and endothelial cells, contributing to inflammatory tissue injury and explaining the tissue hypoxia paradigm based on microvascular dysfunction. An impaired mitochondrial cellular oxygen utilization, rather than inadequate oxygen delivery, was claimed to play a more important role in the development of multisystem organ dysfunction syndrome. Anyway, it seems plausible that reactive oxygen species can mediate the pathophysiologic processes occurring in sepsis. However, the consensus guidelines for the management of patients with these conditions do not include the enhancement of antioxidant potential. Therefore, further investigation is needed to support interventions aimed to attenuate the severity of the systemic compromise by abrogating the mechanism of oxidative damage. Antioxidant supplementation currently in use lacks a mechanistic support. Specific pharmacologic targets, such as mitochondria or Nicotinamide Adenine Dinucleotide Phospate-Oxidase (NADPH) oxidase system, need to be explored. Furthermore, the early recognition of oxidative damage in these seriously ill patients and the usefulness of oxidative stress biomarkers to define a cut point for more successful therapeutic antioxidant interventions to be instituted would offer a new strategy to improve the outcome of critically ill children.     

RNA knockdown as a potential therapeutic strategy in Parkinson's disease

Parkinson's disease is a prevalent progressive degenerative disorder of the elderly. There is a current need for novel therapeutic strategies because the standard levodopa pharmacotherapy is only temporarily efficacious. Recently, there have been some high-profile successful preclinical results obtained in animal models of neurological disorders using small interfering RNAs delivered by viral vectors. RNA interference can theoretically be applied to Parkinson's disease since over-expression of various proteins is known to kill the dopamine neurons of the substantia nigra in animal models and in familial forms of Parkinson's disease. Potential RNA interfering strategies and caveats are discussed in this review.     

TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis

TNF-alpha (tumour necrosis factor-alpha) is known to play a critical role in the pathogenic mechanisms of a number of chronic inflammatory diseases, including RA (rheumatoid arthritis), Crohn's disease and psoriasis. The notion that TNF-alpha is released in allergic responses from both mast cells and macrophages via IgE-dependent mechanisms, the demonstration that elevated levels of TNF-alpha are frequently observed in bronchoalveolar fluid of asthmatic subjects undergoing allergen challenge and the results from exposure studies of TNF-alpha in vivo showing increases in airway responsiveness in both normal and asthmatic subjects emphasize the importance of TNF-alpha in the initiation of allergic asthmatic airway inflammation and the generation of airway hyper-responsiveness. Drugs targeting TNF-alpha have been developed to neutralize the deleterious effects of this inflammatory cytokine and have proved to be safe and effective in the treatment of patients with RA, Crohn's disease and psoriasis refractory to conventional treatments. Biological therapies blocking TNF-alpha are likely to constitute a considerable advance in the management of those difficult cases of asthma that are particularly resistant to typical treatment modalities. In this review article, we intend to address the potential role of TNF-alpha in asthma and to put forward the idea that drugs that have been developed to neutralize the deleterious effects of TNF-alpha may also be useful in the management of chronic severe asthma.     

Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases

In the adult mammalian brain, new neurons are continuously generated from a proliferating population of neural progenitor/stem cells and become incorporated into the existing neuronal circuitry via a process termed adult neurogenesis. The existence of active functional adult neurogenesis raises the exciting possibility that manipulating endogenous neural progenitors, or transplanting the progeny of exogenously expanded neural progenitors, may lead to successful cell replacement therapies for various degenerative neurological diseases. Significant effort is being made to decipher the mechanisms regulating adult neurogenesis, which may allow us to translate this endogenous neuronal replacement system into therapeutic interventions for neurodegenerative diseases. This review focuses on adult neurogenesis as a strategy to derive potential therapies, and discusses future directions in the field.