Free Radical Burden Research Articles

Two Faces of Heme Catabolic Pathway in Newborns: A Potential Role of Bilirubin and Carbon Monoxide in Neonatal Inflammatory Diseases.

In an infant's body, all the systems undergo significant changes in order to adapt to the new, extrauterine environment and challenges which it poses. Fragile homeostasis can be easily disrupted as the defensive mechanisms are yet imperfect. The activity of antioxidant enzymes, i.e., superoxide dismutase, catalase, and glutathione peroxidase, is low; therefore, neonates are especially vulnerable to oxidative stress. Free radical burden significantly contributes to neonatal illnesses such as sepsis, retinopathy of premature, necrotizing enterocolitis, bronchopulmonary dysplasia, or leukomalacia. However, newborns have an important ally—an inducible heme oxygenase-1 (HO-1) which expression rises rapidly in response to stress stimuli. HO-1 activity leads to production of carbon monoxide (CO), free iron ion, and biliverdin; the latter is promptly reduced to bilirubin. Although CO and bilirubin used to be considered noxious by-products, new interesting properties of those compounds are being revealed. Bilirubin proved to be an efficient free radicals scavenger and modulator of immune responses. CO affects a vast range of processes such as vasodilatation, platelet aggregation, and inflammatory reactions. Recently, developed nanoparticles consisting of PEGylated bilirubin as well as several kinds of molecules releasing CO have been successfully tested on animal models of inflammatory diseases. This paper focuses on the role of heme metabolites and their potential utility in prevention and treatment of neonatal diseases.

EFFECT OF MELATONIN ON HYPERTENSION AND DIABETES INDUCED EXPERIMENTALLY IN ADULT MALE ALBINO RATS

Background: Diabetes Mellitus is the most common endocrine disorder. It is a pathological state leads to long term complications causing damage of different tissue and organs as heart and blood vessels. Hypertension is one of the leading causes of mortality and morbidity. Melatonin has extraordinary antioxidant potential and reduce the level of free radical burden on the level of both oxygen and nitrogen species. Objective: Evaluation of melatonin on hypertension and diabetes induced experimentally in adult male albino rats. Materials and Methods: Seventy adult male albino rats of local strain were divided into equal seven groups as follow: Group I: served as control group received normal saline, Group II: diabetic group, Group III: hypertensive group, Group IV: Diabetic-hypertensive group, Group V: diabetic-melatonin-treated group, Group VI: Hypertensive-melatonin-treated group and Group VII: Diabetic-hypertensive-melatonin-treated group. At the end of experimental period, blood samples were obtained for detwrmination of glycated hemoglobin, plasma glucose, serum lipid profile (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglyceride (TG)), serum insulin, serum urea and serum creatinine levels. Measurments of blood pressure were performed for the hypertensive rats. Also, cardiac muscles samples were obtained for histopathology study. Results: STZ led to significant increase in blood glucose, glycated hemoglobin, cholesterol, TG, LDL, serum urea and serum creatinine levels associated with significant decrease in serum insulin level.Cadmium led to significant increase in total cholesterol, TG, LDL, serum urea and serum creatinine levels associated with significant increase in blood pressure. Melatonin treatment led to significant decrease of blood glucose, glycated hemoglobin, total cholesterol, TG, LDL, serum urea and serum creatinine levels associated with significant increase in serum insulin level associated with significant decrease blood pressure. Conclusion: Melatonin has a protective effect against cardiac muscle abnormalities in diabetic, diabetic-hypertensive and hypertensive rats due to its antioxidant properties.

EFFECT OF MELATONIN ON HYPERTENSION AND DIABETES INDUCED EXPERIMENTALLY IN ADULT MALE ALBINO RATS

Background: Diabetes Mellitus is the most common endocrine disorder. It is a pathological state leads to long term complications causing damage of different tissue and organs as heart and blood vessels. Hypertension is one of the leading causes of mortality and morbidity. Melatonin has extraordinary antioxidant potential and reduce the level of free radical burden on the level of both oxygen and nitrogen species. Objective: Evaluation of melatonin on hypertension and diabetes induced experimentally in adult male albino rats. Materials and Methods: Seventy adult male albino rats of local strain were divided into equal seven groups as follow: Group I: served as control group received normal saline, Group II: diabetic group, Group III: hypertensive group, Group IV: Diabetic-hypertensive group, Group V: diabetic-melatonin-treated group, Group VI: Hypertensive-melatonin-treated group and Group VII: Diabetic-hypertensive-melatonin-treated group. At the end of experimental period, blood samples were obtained for detwrmination of glycated hemoglobin, plasma glucose, serum lipid profile (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglyceride (TG)), serum insulin, serum urea and serum creatinine levels. Measurments of blood pressure were performed for the hypertensive rats. Also, cardiac muscles samples were obtained for histopathology study. Results: STZ led to significant increase in blood glucose, glycated hemoglobin, cholesterol, TG, LDL, serum urea and serum creatinine levels associated with significant decrease in serum insulin level.Cadmium led to significant increase in total cholesterol, TG, LDL, serum urea and serum creatinine levels associated with significant increase in blood pressure. Melatonin treatment led to significant decrease of blood glucose, glycated hemoglobin, total cholesterol, TG, LDL, serum urea and serum creatinine levels associated with significant increase in serum insulin level associated with significant decrease blood pressure. Conclusion: Melatonin has a protective effect against cardiac muscle abnormalities in diabetic, diabetic-hypertensive and hypertensive rats due to its antioxidant properties.

Effects of trichotecene mycotoxins on gene expression and activity of glutathione redox system in common carp (Cyprinus carpio L.)

Event Abstract Back to Event Effects of trichotecene mycotoxins on gene expression and activity of glutathione redox system in common carp (Cyprinus carpio L.) Csilla Pelyhe1*, Benjámin Kövesi1, Erika Zándoki2, Balázs Kovács3, Miklós Mézes1 and Krisztián Balogh1 1 Szent István University, Department of Nutrition, Hungary 2 Hungarian Academy of Sciences, Kaposvár University, Mycotoxins in the Food Chain Research Group, Hungary 3 Szent István University, Department of Aquaculture, Hungary The purpose of present study was to evaluate the short- and long-term effects of T-2 toxin and deoxynivalenol (DON) in common carp. Short-term effect was evaluated using single oral doses of DON or T-2 toxin of 0.25, 0.50 or 3.00 mg/kg b.w.. Experimentally contaminated or control complete feed was given by gavage directly into the stomach. Hepatopancreas samples were taken from 6 carps of each group at every 8th hour during a 24-hour long experimental period. The long-term effect was evaluated in 4 weeks in a feeding trial using 0.05 mg T-2 toxin/kg b.w. and 0.06 mg DON/kg b.w., where hepatopancreas samples were taken from 6 carps of each group weekly. Reduced glutathione (GSH) concentration and activities of glutathione-peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) were measured. In addition, expressions of phospholipid hydroperoxide glutathione peroxidase (GPx4) genes (gpx4a and gpx4b) were analyzed. Lipid peroxidation was followed by the determination the amount of conjugated dienes (CDs) and -trienes (CTs) and malondialdehyde (MDA). Short-term exposure showed that both of the investigated mycotoxins caused rapid changes in the lipid peroxidation processes in the hepatopancreas, but the emerging free radical burden quickly activated the glutathione redox system, so the end-product of the lipid peroxidation (MDA) did not elevate significantly in the 24-hour period. Expression of the genes decreased after 8 hours and later increased during the 24-hour period. As effect of long-term exposure, the glutathione redox system showed decreased levels in T-2 toxin treated group, but the markers of lipid peroxidation processes did not elevate. Expression of the investigated genes showed dual response during the experiment. The results revealed that glutathione redox system eliminated effectively the peroxidative effect of the investigated mycotoxins in the applied doses and periods. Acknowledgements The research was supported by the National Scientific Research Fund (OTKA PD104823). Keywords: T-2 Toxin, Deoxynivalenol (DON), Antioxidant Enzymes, common carp, Glutathione redox system, gpx4 genes, Gene Expression Conference: XV European Congress of Ichthyology, Porto, Portugal, 7 Sep - 11 Sep, 2015. Presentation Type: Oral Presentation Topic: Physiology, Behavior and Toxicology Citation: Pelyhe C, Kövesi B, Zándoki E, Kovács B, Mézes M and Balogh K (2015). Effects of trichotecene mycotoxins on gene expression and activity of glutathione redox system in common carp (Cyprinus carpio L.). Front. Mar. Sci. Conference Abstract: XV European Congress of Ichthyology. doi: 10.3389/conf.fmars.2015.03.00028 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Oct 2015; Published Online: 04 Nov 2015. * Correspondence: Miss. Csilla Pelyhe, Szent István University, Department of Nutrition, Gödöllo, 2100, Hungary, pelyhe.csilla@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Csilla Pelyhe Benjámin Kövesi Erika Zándoki Balázs Kovács Miklós Mézes Krisztián Balogh Google Csilla Pelyhe Benjámin Kövesi Erika Zándoki Balázs Kovács Miklós Mézes Krisztián Balogh Google Scholar Csilla Pelyhe Benjámin Kövesi Erika Zándoki Balázs Kovács Miklós Mézes Krisztián Balogh PubMed Csilla Pelyhe Benjámin Kövesi Erika Zándoki Balázs Kovács Miklós Mézes Krisztián Balogh Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Peripheral and central effects of melatonin on blood pressure regulation.

The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology.

The effect of continuous flow left ventricular assist device (CF-LVAD) implantation on serum uric acid levels

The association between congestive heart failure and hyperuricemia is well known [1]. Furthermore, hyperuricemia has also shown to be independently predictive of poor long term outcomes in heart failure, although the exact mechanism of this contribution is unclear [2,3]. A leading hypothesis is that activation of the xanthine oxidase pathway causes an increase in free radical burden, which has been shown to mediate endothelial dysfunction.[4] It has therefore been proposed that xanthine oxidase inhibitors could function therapeutically, though results from these studies have been mixed [5,6].

Predictive Chemometric Modeling of DPPH Free Radical-Scavenging Activity of Azole Derivatives Using 2D- and 3D-Quantitative Structure–Activity Relationship Tools

The endogenous antioxidants often fail to manage the systemic free radical overload resulting from extensive exposure to environmental pollutants and improper diet. Such free-radical burden over a prolonged period leads to oxidative stress, which in turn, promotes an array of fatal diseases. Five different in silico methodologies have been employed here for a series of azole derivatives, which identify the essential structural attributes of the molecules and quantify the contributions of the prime molecular prerequisites for designing compounds with improved antioxidant activity. The importance of the different constituents is quantitatively analyzed using the descriptor-based quantitative structure-activity relationship and group-based quantitative structure-activity relationship models while the pharmacophore, comparative molecular similarity index analysis and hologram quantitative structure-activity relationship models serve as essential query tools for screening of azole compounds in order to select potent antioxidant molecules.

Safety Survey of Intranasal Glutathione

Glutathione depletion has been documented in several disease states, and exogenous administration has been hypothesized to have therapeutic potential for some conditions. In an effort to reach target tissues of the sinuses and central nervous system (CNS), glutathione is being prescribed as an intranasal spray, although no literature exists to support this mode of administration. The objective of this study was to describe patient-reported outcomes in a population of individuals who have been prescribed intranasal reduced glutathione, (in)GSH. A survey was designed to assess individuals' perception of tolerability, adverse events, and health benefits associated with (in)GSH use. Using a pharmacy database, 300 individuals were randomly selected to receive a survey; any individual who had received one or more prescriptions for (in)GSH between March 2009 and March 2011 was eligible for participation. Seventy (70) individuals returned the survey (23.3% response rate) from 20 different states. Reported indications for (in)GSH prescriptions were multiple chemical sensitivity (MCS) (n=29), allergies/sinusitis (n=25), Parkinson disease (PD) (n=7), Lyme disease (n=3), fatigue (n=2), and other (n=10). Of the respondents, 78.8% (n=52) reported an overall positive experience with (in)GSH, 12.1% (n=8) reported having experienced adverse effects, and 62.1% (n=41) reported having experienced health benefits attributable to (in)GSH use. Over 86% of respondents considered the nasal spray to be comfortable and easy to administer. This is the first study to evaluate patient-reported outcomes among individuals across the country who have been prescribed (in)GSH. The majority of survey respondents considered (in)GSH to be effective and without significant adverse effects. (in)GSH should be further evaluated as a method of treating respiratory and CNS diseases where free-radical burden is a suspected contributor to disease progression.

Physiology and pathophysiology of nitrosative and oxidative stress in osteoarthritic joint destruction

Osteoarthritis (OA) is one of the most common chronic diseases, with increasing importance due to increased life expectancy. On a cellular level, the pathophysiology of joint function impairment and ultimate destruction associated with OA remains poorly understood. Free radicals are highly reactive molecules involved in both normal intracellular signal transduction and degenerative cellular processes. An imbalance between the free radical burden and cellular scavenging mechanisms, defined as oxidative stress, has been identified as a relevant factor in OA pathogenesis. This literature review elucidates the involvement of nitrosative and oxidative stress in cellular ageing in joints, cell senescence, and apoptosis. Free radical exposure is known to promote cellular senescence and apoptosis, and the involvement of radical oxygen species (ROS) in inflammation, fibrosis control, and pain nociception has been proven. A relatively novel approach to OA pathophysiology considers the joint to be a dynamic system consisting of 3, continuously interacting compartments, cartilage, synovial tissue, and subchondral bone. Current knowledge concerning free radical involvement in paracrine signalling in OA is reviewed. The interrelationship between oxidative imbalances and OA pathophysiology may provide a novel approach to the comprehension, and therefore modification, of OA disease progression and symptom control.

Oxidative stress in secondary osteoarthritis: from cartilage destruction to clinical presentation?

Due to an increasing life expectance, osteoarthritis (OA) is one of the most common chronic diseases. Although strong efforts have been made to regenerate degenerated joint cartilage, OA is a progressive and irreversible disease up to date. Among other factors the dysbalance between free radical burden and cellular scavenging mechanisms defined as oxidative stress is a relevant part of OA pathogenesis. Here, only little data are available about the mediation and interaction between different joint compartments. The article provides a review of the current literature regarding the influence of oxidative stress on cellular aging, senescence and apoptosis in different joint compartments (cartilage, synovial tissue and subchondral bone). Free radical exposure is known to promote cellular senescence and apoptosis. Radical oxygen species (ROS) involvement in inflammation, fibrosis control and pain nociception has been proven. The data from literature indicates a link between free radical burden and OA pathogenesis mediating local tissue reactions between the joint compartments. Hence, oxidative stress is likely not only to promote cartilage destruction but also to be involved in inflammative transformation, promoting the transition from clinically silent cartilage destruction to apparent OA. ROS induced by exogenous factors such as overload, trauma, local intraarticular lesion and consecutive synovial inflammation cause cartilage degradation. In the affected joint, free radicals mediate disease progression. The interrelationship between oxidative stress and OA etiology might provide a novel approach to the comprehension and therefore modification of disease progression and symptom control.

A colorful explanation for atrial arrhythmias

A colorful explanation for atrial arrhythmias

Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury

Stroke is the third leading cause of death in the United States, yet no neuroprotective agents for treatment are clinically available. There is a pressing need to understand the signaling molecules that mediate ischemic cell death and identify novel neuroprotective targets. Cyclopentenone isoprostanes (IsoPs), formed after free radical-mediated peroxidation of arachidonic acid, are used as markers of stress, but their bioactivity is poorly understood. We have recently shown that 15-A 2t-IsoP is a potent neurotoxin in vitro and increases the free radical burden in neurons. In this work, we demonstrate that 15-A 2t-IsoP is abundantly produced in stroke-infarcted human cortical tissue. Using primary neuronal cultures we found that minimally toxic exposure to 15-A 2t-IsoP does not alter ATP content, but in combination with oxygen glucose deprivation resulted in a significant hyperpolarization of the mitochondrial membrane and dramatically increased neuronal cell death. In the presence of Ca 2+, 15-A 2t-IsoP led to a rapid induction of the permeability transition pore and release of cytochrome c. Taken with our previous work, these data support a model in which ischemia causes generation of reactive oxygen species, calcium influx, lipid peroxidation, and 15-A 2t-IsoP formation. These factors combine to enhance opening of the permeability transition pore leading to cell death subsequent to mitochondrial cytochrome c release. These data are the first documentation of significant 15-A 2t-IsoP formation after acute ischemic stroke and suggest that the addition of 15-A 2t-IsoP to in vitro models of ischemia may help to more fully recapitulate stroke injury.

Differential Effects of Mitochondrial Heat Shock Protein 60 and Related Molecular Chaperones to Prevent Intracellular β-Amyloid-induced Inhibition of Complex IV and Limit Apoptosis

Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been reported in Alzheimer disease tissue and in cultured cells that overexpress amyloid precursor protein. Mitochondrial dysfunction contributes to neurodegeneration in Alzheimer disease partly through formation of reactive oxygen species and the release of sequestered molecules that initiate programmed cell death pathways. The heat shock proteins (HSP) are cytoprotective against a number of stressors, including accumulations of misfolded proteins and reactive oxygen species. We reported on the property of Hsp70 to protect cultured neurons from cell death caused by intraneuronal beta-amyloid. Here we demonstrate that Hsp60, Hsp70, and Hsp90 both alone and in combination provide differential protection against intracellular beta-amyloid stress through the maintenance of mitochondrial oxidative phosphorylation and functionality of tricarboxylic acid cycle enzymes. Notably, beta-amyloid was found to selectively inhibit complex IV activity, an effect selectively neutralized by Hsp60. The combined effect of HSPs was to reduce the free radical burden, preserve ATP generation, decrease cytochrome c release, and prevent caspase-9 activation, all important mediators of beta-amyloid-induced neuronal dysfunction and death.

Methamphetamine‐induced inhibition of mitochondrial complex II: roles of glutamate and peroxynitrite

High-dose methamphetamine (METH) is associated with long-term deficits in dopaminergic systems. Although the mechanism(s) which contributes to these deficits is not known, glutamate and peroxynitrite are likely to play a role. These factors are hypothesized to inhibit mitochondrial function, increasing the free radical burden and decreasing neuronal energy supplies. Previous studies suggest a role for the mitochondrial electron transport chain (ETC) in mediating toxicity of METH. The purpose of the present studies was to determine whether METH administration selectively inhibits complex II of the ETC in rats. High-dose METH administration (10 mg/kg every 2 h x 4) rapidly (within 1 h) decreased complex II (succinate dehydrogenase) activity by approximately 20-30%. In addition, decreased activity of complex II-III, but not complex I-III, of the mitochondrial ETC was also observed 24 h after METH. This inhibition was not due to direct inhibition by METH or METH-induced hyperthermia and was specific to striatal brain regions. METH-induced decreases in complex II-III were prevented by MK-801 and the peroxynitrite scavenger 5,10,15,20-tetrakis (2,4,6-trimethyl-3,5-sulphonatophenyl) porphinato iron III. These findings provide the first evidence that METH administration, via glutamate receptor activation and peroxynitrite formation, selectively alters a specific site of the ETC.

Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase.

Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 microg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) N(G)-monomethyl-L-arginine (L-NMMA; 2, 4, and 8 micromol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 microg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant vitamin C (6 and 18 mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP. In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers.

Free radicals, atherosclerosis, ageing, and related dysmetabolic pathologies: pathological and clinical aspects.

An excess of free-radical production has been linked to many diseases and to the ageing process. Oxidant by-products of normal metabolism can cause extensive damage to DNA, protein and lipid. Exposure to ultraviolet light, cigarette smoke and other environmental pollutants may also increase the free radical burden. The accumulation of unrepaired oxidative damage products is likely to be a major factor in cellular ageing. Many repair processes are available to the cell, including enzyme and structural defences. The large group of natural antioxidants is also part of a protective mechanism. High consumption of fruit and vegetables in the diet is associated with a lowered risk of degenerative diseases. At present, however, there are few data to support the routine use of exogenous antioxidants to prevent and treat these diseases.

Neuroprotective effects of hypothermia and U-78517F in cerebral ischemia are due to reducing oxygen-based free radicals: an electron paramagnetic resonance study with gerbils.

Free radicals are implicated as causative agents in various forms of tissue destruction. Considerable circumstantial evidence suggests that oxygen-based free radicals generated as blood flow returns to formerly ischemic brain areas are mainly responsible for the neurodegeneration that follows periods of cerebral ischemia. In general, oxygen-based free radicals are highly reactive and exist for only a brief period of time. This makes the direct measurement of many of these free radicals rather difficult. Much of the current knowledge of free radicals in cerebral ischemia is based on observations of chemical changes brought about by the free radicals rather than on direct observations of the free radicals themselves. Low temperature electron paramagnetic resonance spectroscopy is one method that allows the direct study of free radicals. Compared to samples from sham-operated controls, samples of hippocampus taken from gerbils exposed to 15 min of forebrain ischemia followed by 15 min of reperfusion, frozen in liquid nitrogen less than 20 sec after sacrifice, and scanned by low temperature (100 K) electron paramagnetic resonance, show a significant increase in oxygen-based free radicals and a decrease in carbon-based ubiquinone-like free radicals. The ischemia-induced increase in oxygen-based free radicals is prevented by the intraperitoneal injection of the antioxidant drug U-78517F at the start of reperfusion and by hypothermia. However, neither intervention alters the ischemia-induced reduction in the ubiquinone-like free radicals. This suggests that the neuroprotective actions of hypothermia and U-78517F include a direct reduction in the oxygen-based free radical burden of the post-ischemic tissue.

Free radical formation in autopsy samples of Alzheimer and control cortex

The formation of free radicals in homogenates of frontal cortex from brains taken at autopsy and verified histologically to be from five patients with Alzheimer's disease or from six age matched normal controls, was measured by electron paramagnetic resonance spectroscopy. During incubation at 37°C, the formation of free radicals by Alzheimer's samples was 22% higher (P < 0.05) than controls. Following incubation in the presence of ferrous sulfate (200 μM), samples of Alzheimer's frontal cortex produced nearly 50% more free radicals than did controls (P < 0.01). Although these post mortem in vitro observations are consistent with an increased free radical burden in tissue from patients with Alzheimer's disease, that comparable differences exist in vivo between Alzheimer's patients and non-demented people remains to be demonstrated.

Physiological Role of Antioxidants in the Immune System

Diets contain naturally occurring antioxidant compounds that can stabilize highly reactive, potentially harmful molecules called free radicals. Free radicals are generated during normal cellular metabolism and result from the metabolism of certain drugs or xenobiotics. Exposure to UV light, cigarette smoke, and other environmental pollutants also increases the body's free radical burden. The harmful activities of free radicals are associated with damage to membranes, enzymes, and DNA. The ability of antioxidants to destroy free radicals protects the structural integrity of cells and tissues. This review focuses on data indicating that the functions of the human immune system depend on the intake of micronutrients, which can act as antioxidants. Recent clinical trials have found that antioxidant supplementation can significantly improve certain immune responses. Specifically, supplementation with vitamins C, E, and A or β-carotene increased the activation of cells involved in tumor immunity in the elderly. Supplementation with the antioxidant vitamins also protected immune responses in individuals exposed to certain environmental sources of free radicals. Supplementation with vitamin A, a relatively weak antioxidant, decreases morbidity and mortality associated with measles infections in children.