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1.  Oxidative Toxicity in Neurodegenerative Diseases: Role of Mitochondrial Dysfunction and Therapeutic Strategies 
Journal of Toxicology  2011;2011:683728.
Besides fluorine, oxygen is the most electronegative element with the highest reduction potential in biological systems. Metabolic pathways in mammalian cells utilize oxygen as the ultimate oxidizing agent to harvest free energy. They are very efficient, but not without risk of generating various oxygen radicals. These cells have good antioxidative defense mechanisms to neutralize these radicals and prevent oxidative stress. However, increased oxidative stress results in oxidative modifications in lipid, protein, and nucleic acids, leading to mitochondrial dysfunction and cell death. Oxidative stress and mitochondrial dysfunction have been implicated in many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and stroke-related brain damage. Research has indicated mitochondria play a central role in cell suicide. An increase in oxidative stress causes mitochondrial dysfunction, leading to more production of reactive oxygen species and eventually mitochondrial membrane permeabilization. Once the mitochondria are destabilized, cells are destined to commit suicide. Therefore, antioxidative agents alone are not sufficient to protect neuronal loss in many neurodegenerative diseases. Combinatorial treatment with antioxidative agents could stabilize mitochondria and may be the most suitable strategy to prevent neuronal loss. This review discusses recent work related to oxidative toxicity in the central nervous system and strategies to treat neurodegenerative diseases.
PMCID: PMC3139184  PMID: 21785590
2.  Recent Advances on the Neuroprotective Potential of Antioxidants in Experimental Models of Parkinson’s Disease 
Parkinson’s disease (PD), a neurodegenerative movement disorder of the central nervous system (CNS) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Although the etiology of PD is not completely understood and is believed to be multifactorial, oxidative stress and mitochondrial dysfunction are widely considered major consequences, which provide important clues to the disease mechanisms. Studies have explored the role of free radicals and oxidative stress that contributes to the cascade of events leading to dopamine cell degeneration in PD. In general, in-built protective mechanisms consisting of enzymatic and non-enzymatic antioxidants in the CNS play decisive roles in preventing neuronal cell loss due to free radicals. But the ability to produce these antioxidants decreases with aging. Therefore, antioxidant therapy alone or in combination with current treatment methods may represent an attractive strategy for treating or preventing the neurodegeneration seen in PD. Here we summarize the recent discoveries of potential antioxidant compounds for modulating free radical mediated oxidative stress leading to neurotoxicity in PD.
PMCID: PMC3431881  PMID: 22949883
Parkinson’s disease; oxidative stress; free radicals; antioxidants; neuroprotection
3.  Oxidatively Generated DNA Damage Following Cu(II)-Catalysis of Dopamine and Related Catecholamine Neurotransmitters and Neurotoxins: Role of Reactive Oxygen Species1 
Free radical biology & medicine  2010;50(1):139-147.
There is increasing evidence supporting a causal role of oxidatively damaged DNA in neurodegeneration during the natural aging process and neurodegenerative diseases such as Parkinson’s and Alzheimer’s. The presence of redox-active catecholamine neurotransmitters coupled with the localization of catalytic copper to DNA suggests a plausible role for these agents in the induction of oxidatively generated DNA damage. In this study we have investigated the role of Cu(II)-catalyzed oxidation of several catecholamine neurotransmitters and related neurotoxins to induce oxidatively generated DNA damage. Auto-oxidation of all catechol neurotransmitters and related congeners tested resulted in the formation of nearly a dozen oxidation DNA products resulting in a decomposition pattern that was essentially identical for all agents tested. The presence of Cu(II), and to a lesser extent Fe(III), had no effect on the decomposition pattern but substantially enhanced the DNA product levels by up to 75 fold, with dopamine producing the highest levels of unidentified oxidation DNA products (383 ± 46 adducts/106 nucleotides), comparable to 8-oxo-7,8-dihydro-2′-deoxyguanosine levels under the same conditions (122 ± 19 adducts/106 nucleotides). The addition of sodium azide, 2,2,6,6-tetramethyl-4-piperidone, tiron, catalase, bathocuproine or methional to the dopamine/Cu(II) reaction mixture resulted in a substantial decrease (>90%) in oxidation DNA product levels, indicating a role of singlet oxygen, superoxide, H2O2, Cu(I) and Cu(I)OOH in their formation. While the addition of N-tert-butyl-α-phenylnitrone significantly decreased (67%) dopamine-mediated oxidatively damaged DNA, three other hydroxyl radical scavengers, ascorbic acid, sodium benzoate and mannitol, had little to no effect on these oxidation DNA product levels, suggesting that free hydroxyl radicals may have limited involvement in this dopamine/Cu(II)-mediated oxidatively generated DNA damage. These studies suggest a possible contributory role of oxidatively generated DNA damage by dopamine and related catechol neurotransmitters/neurotoxins in neurodegeneration and cell death. We also found that a naturally occurring broad spectrum antioxidant, ellagic acid, was substantially effective (nearly 50% inhibition) at low doses (1 μM) at preventing this dopamine/Cu(II)-mediated oxidatively generated DNA damage. Since dietary ellagic acid has been found to reduce oxidative stress in rat brains, a neuro-protective role of this polyphenol is plausible.
PMCID: PMC3353411  PMID: 21075203
Neurotransmitters; Dopamine; Catecholamines; Oxidative DNA adducts; 32P-Postlabeling
4.  Antioxidant Enzyme Gene Transfer for Ischemic Diseases 
Advanced drug delivery reviews  2009;61(4):351-363.
The balance of redox is pivotal for normal function and integrity of tissues. Ischemic insults occur as results of a variety of conditions, leading to an accumulation of reactive oxygen species (ROS) and an imbalanced redox status in the tissues. The oxidant stress may activate signaling mechanisms provoking more toxic events, and eventually cause tissue damage. Therefore, treatments with antioxidants, free radical scavengers and their mimetics, as well as gene transfer approaches to overexpress antioxidant genes represent potential therapeutic options to correct the redox imbalance. Among them, antioxidant gene transfer may enhance the production of antioxidant scavengers, and has been employed to experimentally prevent or treat ischemic injury in cardiovascular, pulmonary, hepatic, intestinal, central nervous or other systems in animal models. With improvements in vector systems and delivery approaches, innovative antioxidant gene therapy has conferred better outcomes for myocardial infarction, reduced restenosis after coronary angioplasty, improved the quality and function of liver grafts, as well as outcome of intestinal and cerebral ischemic attacks. However, it is crucial to be mindful that like other therapeutic armentarium, the efficacy of antioxidant gene transfer requires extensive preclinical investigation before it can be used in patients, and that it may have unanticipated short- or long-term adverse effects. Thus, it is critical to balance between the therapeutic benefits and potential risks, to develop disease-specific antioxidant gene transfer strategies, to deliver the therapy with an optimal time window and in a safe manner. This review attempts to provide the rationale, the most effective approaches and the potential hurdles of available antioxidant gene transfer approaches for ischemic injury in various organs, as well as the possible directions of future preclinical and clinical investigations of this highly promising therapeutic modality.
PMCID: PMC2691416  PMID: 19233238
ischemia/reperfusion; ischemic injury; oxidant stress; reactive oxygen species; antioxidant; gene transfer; gene therapy; liver; heart; lung; central nervous system; intestine; superoxide dismutase; catalase; glutathione peroxidase; heme oxygenase-1; xanthine oxidase; NADPH oxidase
5.  Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations 
Experimental eye research  2008;88(2):195-203.
Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself (Lin and Beal, 2006). In the anterior segment of the eye, oxidative stress has been linked to lens cataract (Truscott, 2005) and glaucoma (Tezel, 2006) while in the posterior segment of the eye oxidative stress has been associated with macular degeneration (Hollyfield et al., 2008). Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O2-) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (˙OH), hydrogen peroxide (H2O2) and peroxynitrite (OONO-). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria (Hansford et al., 1997). Generation of superoxide at complex I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane (Kakkar and Singh 2007). While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr) protein repair system and other redox systems play key roles in the function and maintenance of the aging eye.
PMCID: PMC2683477  PMID: 18588875
Mitochondria; Cataract; Macular Degeneration; Oxidative Stress; Reactive Oxygen Species; Aging; Methionine Sulfoxide Reductase
6.  Brain Activity of Thioctic Acid Enantiomers: In Vitro and in Vivo Studies in an Animal Model of Cerebrovascular Injury 
Oxidative stress is an imbalance between the production of free radicals and antioxidant defense mechanisms, potentially leading to tissue damage. Oxidative stress has a key role in the development of cerebrovascular and/or neurodegenerative diseases. This phenomenon is mainly mediated by an enhanced superoxide production by the vascular endothelium with its consequent dysfunction. Thioctic, also known as alpha-lipoic acid (1,2-dithiolane-3-pentanoic acid), is a naturally occurring antioxidant that neutralizes free radicals in the fatty and watery regions of cells. Both the reduced and oxidized forms of the compound possess antioxidant ability. Thioctic acid has two optical isomers designated as (+)- and (−)-thioctic acid. Naturally occurring thioctic acid is the (+)-thioctic acid form, but the synthetic compound largely used in the market for stability reasons is a mixture of (+)- and (−)-thioctic acid. The present study was designed to compare the antioxidant activity of the two enantiomers versus the racemic form of thioctic acid on hydrogen peroxide-induced apoptosis in a rat pheochromocytoma PC12 cell line. Cell viability was evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and free oxygen radical species (ROS) production was assessed by flow cytometry. Antioxidant activity of the two enantiomers and the racemic form of thioctic acid was also evaluated in spontaneously hypertensive rats (SHR) used as an in vivo model of increased oxidative stress. A 3-h exposure of PC12 cells to hydrogen peroxide (H2O2) significantly decreased cell viability and increased levels of intracellular ROS production. Pre-treatment with racemic thioctic acid or (+)-enantiomer significantly inhibited H2O2-induced decrease in cell viability from the concentration of 50 μmol/L and 20 μmol/L, respectively. Racemic thioctic acid and (+)-salt decreased levels of intracellular ROS, which were unaffected by (−)-thioctic acid. In the brain of SHR, the occurrence of astrogliosis and neuronal damage, with a decreased expression of neurofilament 200 kDa were observed. Treatment of SHR for 30 days with (+)-thioctic acid reduced the size of astrocytes and increased the neurofilament immunoreaction. The above findings could contribute to clarify the role played by thioctic acid in central nervous system injury related to oxidative stress. The more pronounced effect of (+)-thioctic acid observed in this study may have practical therapeutic implications worthy of being investigated in further preclinical and clinical studies.
PMCID: PMC3634420  PMID: 23443159
oxidative stress; thioctic acid; brain; spontaneously hypertensive rats; PC12 cells
7.  Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death 
Antioxidants & Redox Signaling  2009;11(3):481-496.
Lysosomes critically regulate the pH-dependent catabolism of extracellular and intracellular macromolecules delivered from the endocytic/heterophagy and autophagy pathways, respectively. The importance of lysosomes to cell survival is underscored not only by their unique ability effectively to degrade metalloproteins and oxidatively damaged macromolecules, but also by the distinct potential for induction of both caspase-dependent and -independent cell death with a compromise in the integrity of lysosome function. Oxidative stress and free radical damage play a principal role in cell death induced by lysosome dysfunction and may be linked to several upstream and downstream stimuli, including alterations in the autophagy degradation pathway, inhibition of lysosome enzyme function, and lysosome membrane damage. Neurons are sensitive to lysosome dysfunction, and the contribution of oxidative stress and free radical damage to lysosome dysfunction may contribute to the etiology of neurodegenerative disease. This review provides a broad overview of lysosome function and explores the contribution of oxidative stress and autophagy to lysosome dysfunction–induced neuron death. Putative signaling pathways that either induce lysosome dysfunction or result from lysosome dysfunction or both, and the role of oxidative stress, free radical damage, and lysosome dysfunction in pediatric lysosomal storage disorders (neuronal ceroid lipofuscinoses or NCL/Batten disease) and in Alzheimer's disease are emphasized. Antioxid. Redox Signal. 11, 481–496.
PMCID: PMC2933567  PMID: 18764739
8.  Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function 
Arthritis Research & Therapy  2005;7(2):R380-R391.
Oxidative stress leads to increased risk for osteoarthritis (OA) but the precise mechanism remains unclear. We undertook this study to clarify the impact of oxidative stress on the progression of OA from the viewpoint of oxygen free radical induced genomic instability, including telomere instability and resulting replicative senescence and dysfunction in human chondrocytes. Human chondrocytes and articular cartilage explants were isolated from knee joints of patients undergoing arthroplastic knee surgery for OA. Oxidative damage and antioxidative capacity in OA cartilage were investigated in donor-matched pairs of intact and degenerated regions of tissue isolated from the same cartilage explants. The results were histologically confirmed by immunohistochemistry for nitrotyrosine, which is considered to be a maker of oxidative damage. Under treatment with reactive oxygen species (ROS; 0.1 μmol/l H2O2) or an antioxidative agent (ascorbic acid: 100.0 μmol/l), cellular replicative potential, telomere instability and production of glycosaminoglycan (GAG) were assessed in cultured chondrocytes. In tissue cultures of articular cartilage explants, the presence of oxidative damage, chondrocyte telomere length and loss of GAG to the medium were analyzed in the presence or absence of ROS or ascorbic acid. Lower antioxidative capacity and stronger staining of nitrotyrosine were observed in the degenerating regions of OA cartilages as compared with the intact regions from same explants. Immunostaining for nitrotyrosine correlated with the severity of histological changes to OA cartilage, suggesting a correlation between oxidative damage and articular cartilage degeneration. During continuous culture of chondrocytes, telomere length, replicative capacity and GAG production were decreased by treatment with ROS. In contrast, treatment with an antioxidative agent resulted in a tendency to elongate telomere length and replicative lifespan in cultured chondrocytes. In tissue cultures of cartilage explants, nitrotyrosine staining, chondrocyte telomere length and GAG remaining in the cartilage tissue were lower in ROS-treated cartilages than in control groups, whereas the antioxidative agent treated group exhibited a tendency to maintain the chondrocyte telomere length and proteoglycan remaining in the cartilage explants, suggesting that oxidative stress induces chondrocyte telomere instability and catabolic changes in cartilage matrix structure and composition. Our findings clearly show that the presence of oxidative stress induces telomere genomic instability, replicative senescence and dysfunction of chondrocytes in OA cartilage, suggesting that oxidative stress, leading to chondrocyte senescence and cartilage ageing, might be responsible for the development of OA. New efforts to prevent the development and progression of OA may include strategies and interventions aimed at reducing oxidative damage in articular cartilage.
PMCID: PMC1065334  PMID: 15743486
cellular senescence; chondrocyte; osteoarthritis; oxidative stress; telomere
9.  Achieving the Balance between ROS and Antioxidants: When to Use the Synthetic Antioxidants 
Free radical damage is linked to formation of many degenerative diseases, including cancer, cardiovascular disease, cataracts, and aging. Excessive reactive oxygen species (ROS) formation can induce oxidative stress, leading to cell damage that can culminate in cell death. Therefore, cells have antioxidant networks to scavenge excessively produced ROS. The balance between the production and scavenging of ROS leads to homeostasis in general; however, the balance is somehow shifted towards the formation of free radicals, which results in accumulated cell damage in time. Antioxidants can attenuate the damaging effects of ROS in vitro and delay many events that contribute to cellular aging. The use of multivitamin/mineral supplements (MVMs) has grown rapidly over the past decades. Some recent studies demonstrated no effect of antioxidant therapy; sometimes the intake of antioxidants even increased mortality. Oxidative stress is damaging and beneficial for the organism, as some ROS are signaling molecules in cellular signaling pathways. Lowering the levels of oxidative stress by antioxidant supplements is not beneficial in such cases. The balance between ROS and antioxidants is optimal, as both extremes, oxidative and antioxidative stress, are damaging. Therefore, there is a need for accurate determination of individual's oxidative stress levels before prescribing the supplement antioxidants.
PMCID: PMC3657405  PMID: 23738047
10.  Effects of antioxidant supplementation on the aging process 
Clinical Interventions in Aging  2007;2(3):377-387.
The free radical theory of aging hypothesizes that oxygen-derived free radicals are responsible for the age-related damage at the cellular and tissue levels. In a normal situation, a balanced-equilibrium exists among oxidants, antioxidants and biomolecules. Excess generation of free radicals may overwhelm natural cellular antioxidant defences leading to oxidation and further contributing to cellular functional impairment. The identification of free radical reactions as promoters of the aging process implies that interventions aimed at limiting or inhibiting them should be able to reduce the rate of formation of aging changes with a consequent reduction of the aging rate and disease pathogenesis. Even if antioxidant supplementation is receiving growing attention and is increasingly adopted in Western countries, supporting evidence is still scarce and equivocal. Major limitations in literature are still needed to be addressed to better evaluate the potential benefits from antioxidant supplementation: 1) an improved understanding of oxidation mechanisms possibly at the basis of the aging process, 2) the determination of reliable markers of oxidative damage and antioxidant status, 3) the identification of a therapeutic window in which an eventual antioxidant supplementation may be beneficial, 4) a deeper knowledge of the antioxidant molecules which in several conditions act as pro-oxidants. In the present paper, after a preliminary introduction to the free radical theory of aging and the rationale of antioxidant supplementation as an anti-aging intervention, we will present an overview of evidence relating antioxidant supplementations with clinical conditions typical of older age (ie, cardiovascular disease, Alzheimer’s disease, cancer). We will also discuss studies that have evaluated whether antioxidant supplementation might improve major outcomes of interest in older persons (ie, physical performance, muscle strength, longevity). Given the large amount of data available on the antioxidant supplementation topic, this overview is not intended to be exhaustive. The aim of this paper is to provide the main basis from which future studies should start and indicate which the main limitations that need to be addressed are.
PMCID: PMC2685276  PMID: 18044188
aging; anti-aging medicine; antioxidant supplementation; oxidative damage
11.  Free Radicals: Emerging Challenge in Environmental Health Research in Childhood and Neonatal Disorders 
Infants and children may undergo severe oxidative stress due to disease state, pre-existing nutritional status, frequent use of oxygen, and lower levels of antioxidant defenses. Antioxidant defenses, made up of intracellular and extra-cellular components, work synergistically to prevent oxidative damage. Total antioxidant activity (TAA) was analyzed by method of ferric reducing antioxidant power assay (FRAP). Patients admitted in Pediatric Dept, RNT Medical College, Udaipur, India were selected for these studies. TAA level in neonates with hypoxic-ischemic-encephalopathy (HIE) stage III and in poor outcome cases was significantly low. Erythrocyte SOD activity level was low in pre-term neonates. TAA level in severely malnourished children at the time of hospital admission was low. This low antioxidant level in severely malnourished children could be multi-factorial viz. low zinc, selenium, vitamin A & C deficiency, recurrent infections, elevated free iron and chronic starvation stage. Delayed recovery of oxidant injury may lead to delayed incomplete recovery at cellular level. In a study of 29 tuberculosis patients TAA level was found to be low in tubercular patients compared with control. TAA level decreased more in CNS tuberculosis compared with other system tuberculosis. In a study of nutritional tremor syndrome TAA, ascorbic acid and α-tocopherol levels were low during pre-tremor phase compared with tremor phase (ATS). Pre-term neonates have incompletely developed antioxidant defenses and are deficient in vitamin E, which is normally derived from maternal circulation at the end of 3rd trimester. Therefore, decreased TAA level in HIE with poor outcome indicates addition of antioxidants in therapeutic strategy. Since rise in TAA in antioxidant supplemented group of severely malnutrition children was higher with good outcome compared with non-supplemented group it would be prudent to supplement antioxidant during nutritional management. These studies have shown that health benefits can be obtained by children with a reduced risk of disease from supplements of antioxidant nutrients. The amounts of optimal supplements in these disorders, whether pharmacologic or large, are to be determined. Further work is needed to show whether modest increases in nutrient intakes in children with these disorders will delay or prevent the complications and improve the outcome. Therefore, available evidence regarding health benefits to be achieved by supplementing antioxidant nutrients is encouraging. Free radical injury and antioxidant deficiency is more common than what we think. Severely malnourished children and children suffering from chronic infections and diseases are at several fold increased risk of antioxidant deficiency and likely to suffer from free radical injury. Appropriate interventions are required in reducing the risk associated with these observations.
PMCID: PMC3807523  PMID: 16968976
Free radicals; antioxidants; malnutrition; environmental health; hypoxia
12.  Anti-Oxidative Effects of Rooibos Tea (Aspalathus linearis) on Immobilization-Induced Oxidative Stress in Rat Brain 
PLoS ONE  2014;9(1):e87061.
Exposure to chronic psychological stress may be related to increased reactive oxygen species (ROS) or free radicals, and thus, long-term exposure to high levels of oxidative stress may cause the accumulation of oxidative damage and eventually lead to many neurodegenerative diseases. Compared with other organs, the brain appears especially susceptible to excessive oxidative stress due to its high demand for oxygen. In the case of excessive ROS production, endogenous defense mechanisms against ROS may not be sufficient to suppress ROS-associated oxidative damage. Dietary antioxidants have been shown to protect neurons against a variety of experimental neurodegenerative conditions. In particular, Rooibos tea might be a good source of antioxidants due to its larger proportion of polyphenolic compounds. An optimal animal model for stress should show the features of a stress response and should be able to mimic natural stress progression. However, most animal models of stress, such as cold-restraint, electric foot shock, and burn shock, usually involve physical abuse in addition to the psychological aspects of stress. Animals subjected to chronic restraint or immobilization are widely believed to be a convenient and reliable model to mimic psychological stress. Therefore, in the present study, we propose that immobilization-induced oxidative stress was significantly attenuated by treatment with Rooibos tea. This conclusion is demonstrated by Rooibos tea’s ability to (i) reverse the increase in stress-related metabolites (5-HIAA and FFA), (ii) prevent lipid peroxidation (LPO), (iii) restore stress-induced protein degradation (PD), (iv) regulate glutathione metabolism (GSH and GSH/GSSG ratio), and (v) modulate changes in the activities of antioxidant enzymes (SOD and CAT).
PMCID: PMC3897768  PMID: 24466326
13.  A New Chiral Pyrrolyl α-Nitronyl Nitroxide Radical Attenuates β-Amyloid Deposition and Rescues Memory Deficits in a Mouse Model of Alzheimer Disease 
Neurotherapeutics  2012;10(2):340-353.
The generation of reactive oxygen species causes cellular oxidative damage, and has been implicated in the etiology of Alzheimer’s disease (AD). L-NNNBP, a new chiral pyrrolyl α-nitronyl nitroxide radical synthesized in our department, shows potential antioxidant effects. The purpose of this study was to investigate the protective effects of L-NNNBP on β-amyloid (Aβ) deposition and memory deficits in an AD model of APP/PS1 mice. In cultured cortical neurons, L-NNNBP acted as an antioxidant by quenching reactive oxygen species, inhibiting lipid peroxidation, nitrosative stress, and stimulating cellular antioxidant defenses. L-NNNBP inhibited cell apoptosis induced by Aβ exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain Aβ deposition and tau phosphorylation in the blinded study on APP/PS1 transgenic mice (1 mM in drinking water, initiated when the mice were 6 months old). The L-NNNBP-treated APP/PS1 mice showed decreased astrocyte activation and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These actions were more potent compared with that of curcumin, a natural product, and TEMPO, a nitroxide radical, which are used as free radical scavengers in clinics. These results proved that the newly synthesized L-NNNBP was an effective therapeutic agent for the prevention and treatment of AD.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0168-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3625382  PMID: 23212232
Reactive oxygen species; Alzheimer disease; Nitroxide radical; L-NNNBP; β-amyloid
14.  NADPH oxidases: novel therapeutic targets for neurodegenerative diseases 
Oxidative stress is a key pathologic factor in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. The failure of free-radical-scavenging antioxidants in clinical trials pinpoints an urgent need to identify and to block major sources of oxidative stress in neurodegenerative diseases. As a major superoxide-producing enzyme complex in activated phagocytes, phagocytic NADPH oxidase (PHOX) is essential for host defense. However, recent preclinical evidence has underscored a pivotal role of over-activated PHOX in chronic neuroinflammation and progressive neurodegeneration. Deficiency in PHOX subunits mitigates neuronal damage induced by diverse insults/stresses relevant to neurodegenerative diseases. More importantly, the suppression of PHOX activity correlates with less neuronal impairment in models of neurodegenerative diseases. The discovery of PHOX and non-phagocytic NADPH oxidases in astroglia and neurons further reinforces the critical role of NADPH oxidases in oxidative stress-mediated chronic neurodegeneration. Thus, proper modulation of NADPH oxidase activity might hold therapeutic potential for currently incurable neurodegenerative diseases.
PMCID: PMC3477578  PMID: 22503440
15.  Antioxidants, Oxidative Damage and Oxygen Deprivation Stress: a Review 
Annals of Botany  2003;91(2):179-194.
Oxidative stress is induced by a wide range of environmental factors including UV stress, pathogen invasion (hypersensitive reaction), herbicide action and oxygen shortage. Oxygen deprivation stress in plant cells is distinguished by three physiologically different states: transient hypoxia, anoxia and reoxygenation. Generation of reactive oxygen species (ROS) is characteristic for hypoxia and especially for reoxygenation. Of the ROS, hydrogen peroxide (H2O2) and superoxide (O2·–) are both produced in a number of cellular reactions, including the iron‐catalysed Fenton reaction, and by various enzymes such as lipoxygenases, peroxidases, NADPH oxidase and xanthine oxidase. The main cellular components susceptible to damage by free radicals are lipids (peroxidation of unsaturated fatty acids in membranes), proteins (denaturation), carbohydrates and nucleic acids. Consequences of hypoxia‐induced oxidative stress depend on tissue and/or species (i.e. their tolerance to anoxia), on membrane properties, on endogenous antioxidant content and on the ability to induce the response in the antioxidant system. Effective utilization of energy resources (starch, sugars) and the switch to anaerobic metabolism and the preservation of the redox status of the cell are vital for survival. The formation of ROS is prevented by an antioxidant system: low molecular mass antioxidants (ascorbic acid, glutathione, tocopherols), enzymes regenerating the reduced forms of antioxidants, and ROS‐interacting enzymes such as SOD, peroxidases and catalases. In plant tissues many phenolic compounds (in addition to tocopherols) are potential antioxidants: flavonoids, tannins and lignin precursors may work as ROS‐scavenging compounds. Antioxidants act as a cooperative network, employing a series of redox reactions. Interactions between ascorbic acid and glutathione, and ascorbic acid and phenolic compounds are well known. Under oxygen deprivation stress some contradictory results on the antioxidant status have been obtained. Experiments on overexpression of antioxidant production do not always result in the enhancement of the antioxidative defence, and hence increased antioxidative capacity does not always correlate positively with the degree of protection. Here we present a consideration of factors which possibly affect the effectiveness of antioxidant protection under oxygen deprivation as well as under other environmental stresses. Such aspects as compartmentalization of ROS formation and antioxidant localization, synthesis and transport of antioxidants, the ability to induce the antioxidant defense and cooperation (and/or compensation) between different antioxidant systems are the determinants of the competence of the antioxidant system.
PMCID: PMC4244988  PMID: 12509339
Review; anoxia; hypoxia; reactive oxygen species; antioxidant; lipid peroxidation; adaptation; oxygen deprivation stress
16.  Free radical scavengers in anaesthesiology and critical care 
Indian Journal of Anaesthesia  2012;56(3):227-233.
Free radicals are highly reactive and unstable compounds. These highly reactive molecules cause oxidative damage to cellular components such as DNA, proteins and lipids. They play central role in the mechanism of cell injury and cell death. Free radical scavengers either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in critical illnesses characterized by tissue ischaemia-reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome, acute lung injury. Several clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. Antioxidant supplementation at an early stage of illness may lead to improved therapies in the treatment of critically ill patients. Several intravenous anaesthetic drugs act as reactive oxygen species scavengers. Anaesthetic preconditioning is of particular interest to anaesthesiologist, in which lasting protection of myocardium is elicited by brief exposure to a inhalational anaesthetic agent. These anasthetics may also mediate protective effects in other organs, such as the brain and kidney It is important for the anaesthesiologist to understand the mechanism of damage caused by free radicals and how free radical scavengers work so that this knowledge can be applied to varied pathological conditions. The topic was hand searched in text books and electronically searched from PubMed and Google scholar using text words.
PMCID: PMC3425280  PMID: 22923819
Anaesthesiology; antioxidants; critical care; free radicals; oxidative stress
17.  Antioxidants Halt Axonal Degeneration in a Mouse Model of X-Adrenoleukodystrophy 
Annals of Neurology  2011;70(1):84-92.
Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD).
X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD.
Here, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.
We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor. Ann Neurol 2011;
PMCID: PMC3229843  PMID: 21786300
18.  Comment on: Anti-Oxidative Stress Activity of Stachys lavandulifolia Aqueous Extract in Humans 
Cell Journal (Yakhteh)  2013;15(3):272-273.
A recent article by Rahzani et al. (1) published in the esteemed Cell Journal reported the antioxidative stress activity of Stachys lavandulifolia aqueous extract in humans and suggested its consumption as a supplement in the management of diseases related to oxidative stress. We would like to emphasize some of the limitations regarding antioxidant supplementation, in general, and Stachys lavandulifolia, in particular.
It has been established that oxidative stress is involved in the development of a wide variety of chronic and degenerative diseases such as cancer, Parkinson and Alzheimer’s (2-5). Antioxidants are also effective in the prevention or reduction of adverse effects related to medication usage (5-10). However, they may potentially have deleterious effects. A major concern of antioxidant supplementation is their harmful effect on reactive oxygen species (ROS) production (prooxidant action), particularly when precise modulation of ROS levels are necessary for normal cell function (4-10). In fact, it has been reported that antioxidants may exhibit pro-oxidant activity under specific conditions. Of particular importance are redox conditions the dosage and the presence of free transition metals at cellular sites. For example, the antioxidant vitamin C in the presence of ferric iron may act as a potent mediator of lipid peroxidation. It has been suggested that β-carotene sometimes acts as a pro-oxidant in the lungs of smokers and similarly vitamin C may increase DNA damage in humans (11, 12). Therefore, it is necessary to take into account the bioavailability and differential activities of antioxidant compounds before their administration.
Other than general considerations for antioxidant consumption, the aspects of each particular antioxidant should also be considered (3, 13, 14). Recently, in a preclinical study we reported the renal toxicity of hydroalcoholic extract of Stachys lavandulifolia Vahl in Wistar rats (15). In this experimental study we randomly assigned 100 male Wistar rats to five equal groups, one control and four experimental. Animals received intraperitoneal injections of saline or Stachys lavandulifolia extract (50, 100, 150, 200 mg/kg) for one month after which blood samples were collected from half of the animals from each group. Other animals received no injections for one additional month, then blood samples were obtained. In the groups that Stachys lavandulifolia Vahl extracts were used for one month we observed mild degeneration of renal tubular epithelial cells (6, 9). In the second month of the study these histologic lesions significantly increased (p< 0.05). We concluded that hydroalcoholic extract of Stachys lavandulifolia has renal tubular toxicity which might continue following drug discontinuation (6, 9, 15).
Therefore, although antioxidant supplements generally have beneficial effects, as a caution it is advised to only consume such supplements under medical supervision in order to avoid any potential negative effects.
PMCID: PMC3769611  PMID: 24027670
Stachys lavandulifolia; Toxicity; Nephrotoxicity; Antioxidant
19.  Restoration of tryptophan hydroxylase functions and serotonin content in the Atlantic croaker hypothalamus by antioxidant treatment during hypoxic stress 
Antioxidants are prototypical scavengers of oxygen-free radicals and have been shown to prevent neuroendocrine dysfunction in vertebrates during oxidative stress. In the present study, we investigated whether antioxidant treatment can reverse hypoxia-induced down-regulation of hypothalamic tryptophan hydroxylase (TPH) and serotonergic functions in Atlantic croaker. Hypothalamic neuronal contents of TPH-1 and TPH-2 proteins, serotonin (5-hydroxytryptamine, 5-HT) and its precursor, 5-hydroxytryptophan (5-HTP) as well as hypothalamic TPH-1 and TPH-2 mRNA expression and TPH activity were measured in croaker after exposure to hypoxia and treatment with pharmacological agents. Multiple injections of N-ethylmaleimide, a sulfhydryl alkylating agent, caused comparable decreases in hypothalamic TPHs functions and 5-HT contents to that induced by hypoxia exposure (dissolved oxygen: 1.7 mg/L for 4 weeks) which were partially restored by repeated injections with a nitric oxide synthase (NOS)-inhibitor and/or vitamin E. Double-labeled immunohistochemical results showed that TPHs and 5-HT neurons were co-expressed with neuronal NOS (nNOS, a neuroenzyme) that catalyzes the production of nitric oxide, a free radical, in hypothalamic neurons. These results suggest that hypoxia-induced impairment of TPH and serotonergic functions are mediated by nNOS and involve the generation of free radicals and a decrease in the antioxidant status. This study provides, to our knowledge, the first evidence of a protective role for an antioxidant in maintaining neural TPHs functions and 5-HT regulation in an aquatic vertebrate during hypoxic stress.
PMCID: PMC4038761  PMID: 24910592
neuroenzyme; neurotransmitter; antioxidant; fish; brain; hypoxia
20.  Manganese Induces Oxidative Stress, Redox State Unbalance and Disrupts Membrane Bound ATPases on Murine Neuroblastoma Cells In Vitro: Protective Role of Silymarin 
Neurochemical Research  2011;36(8):1546-1557.
Manganese (Mn) is an essential trace element required for ubiquitous enzymatic reactions. Chronic overexposure to this metal may promote potent neurotoxic effects. The mechanism of Mn toxicity is not well established, but several studies indicate that oxidative stress play major roles in the Mn-induced neurodegenerative processes. Silymarin (SIL) has antioxidant properties and stabilizes intracellular antioxidant defense systems. The aim of this study was to evaluate the toxic effects of MnCl2 on the mouse neuroblastoma cell lines (Neuro-2A), to characterize the toxic mechanism associated with Mn exposure and to investigate whether SIL could efficiently protect against neurotoxicity induced by Mn. A significant increase in LDH release activity was observed in Neuro-2A cells associated with a significant decrease in cellular viability upon 24 h exposure to MnCl2 at concentrations of 200 and 800 μM (P < 0.05) when compared with control unexposed cells. In addition, exposure cells to MnCl2 (200 and 800 μM), increases oxidant biomarkers and alters enzymatic and non enzymatic antioxidant systems. SIL treatment significantly reduced the levels of LDH, nitric oxide, reactive oxygen species and the oxidants/antioxidants balance in Neuro-2A cells as compared to Mn-exposed cells. These results suggested that silymarin is a powerful antioxidant through a mechanism related to its antioxidant activity, able to interfere with radical-mediated cell death. SIL may be useful in diseases known to be aggravated by reactive oxygen species and in the development of novel treatments for neurodegenerative disorders such as Alzheimer or Parkinson diseases.
PMCID: PMC3139064  PMID: 21533646
Manganese; Oxidative stress; Neuro-2A cells; Silymarin; Glutathione
21.  Diapause Formation and Downregulation of Insulin-Like Signaling via DAF-16/FOXO Delays Axonal Degeneration and Neuronal Loss 
PLoS Genetics  2012;8(12):e1003141.
Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO–dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment.
Author Summary
Axonal degeneration and neuronal loss are currently considered crucial pathological factors in neurodegenerative diseases. Therefore, delaying or blocking these procesess is key for neuroprotection. In this work, we used an in vivo approach combining invertebrate (C. elegans) and vertebrate (mice) model systems to identify a novel and unexpected player in the mechanisms of axonal degeneration. Here, we demonstrate that both neuronal somas and axons degenerate through a step dependent on oxidative stress that can be efficiently delayed by genetic downregulation of a pathway controlling oxidative stress resistance. Impressively, we discovered that diapause formation, which is a state related to hibernating conditions, fully prevents neuronal degeneration. We uncovered new players in the degenerative mechanisms of neurons with relevance for several conditions associated to axonal degeneration, such as multiple sclerosis, motoneuron, and Parkinson diseases, offering novel potential targets for neuroprotection.
PMCID: PMC3531479  PMID: 23300463
22.  Oxidative Stress in Aging in the C57B16/J Mouse Cochlea 
Acta oto-laryngologica  2001;121(6):666-672.
Presbycusis is a complex of high frequency hearing loss and disproportionate loss of speech discrimination that is seen concomitantly with physical signs of aging. Among the most extensively characterized strains of mice that show an early hearing loss is the C57B16/J strain, a strain that shows early onset of high frequency hearing loss at age 6 months and complete hearing loss by 1 year of age. The histopathology of this strain consists of loss of hair cells and spiral ganglion neurons in the basal turn, with a progression of loss of hair cells and ganglion neurons towards the apical portion of the cochlea as the animal ages. The process of aging has been extensively studied and although details differ in various organisms the consensus today is that oxidative stress, i.e. free radical-mediated tissue damage, is one of the core mechanisms of aging. Aerobic metabolism results in the creation of hydrogen peroxide and reactive oxygen species. These are normally detoxified by a variety of enzymes and free radical scavengers, including superoxide dismutase (SOD), catalase and glutathione. To determine whether oxidative stress plays a role in the pathophysiology of hearing loss in this mouse model of presbycusis we determined the relative change in mRNA production for selected free radical detoxifying enzymes in the C57B16/J mouse cochlea. Using semi-quantitative RT-PCR with tubulin mRNA as a control, relative levels of antioxidant enzyme mRNAs were determined. There was an overall increase in SOD1 mRNA levels when comparing 1 and 9 month time points, and a transient increase in the expression level of catalase mRNA. B6.CAST+Ahl mice, which carry the C57B16/J genome but receive their Ahl gene from CAST mice, do not show these alteractions in antioxidant enzyme production. Our results suggest that at an age of 9 months, at which point significant hearing loss has developed, the C57B16/J mouse cochlea is exposed to increased levels of free radicals and that the Ahl gene of the C57B16/J mouse mediates this decrease in protective enzymes and therefore increase in levels of oxidative stress.
PMCID: PMC2862210  PMID: 11678164
aging; C57B16/J mouse; oxidative stress; presbycusis
23.  Nitrones as Therapeutics 
Free radical biology & medicine  2008;45(10):1361-1374.
Nitrones have the general chemical formula X-CH=NO-Y. They were first used to trap free radicals in chemical systems and then subsequently in biochemical systems. More recently several nitrones including PBN (α-phenyl-tert-butylnitrone) have been shown to have potent biological activity in many experimental animal models. Many diseases of aging including stroke, cancer development, Parkinson’s disease and Alzheimer’s disease are known to have enhanced levels of free radicals and oxidative stress. Some derivatives of PBN are significantly more potent than PBN and have undergone extensive commercial development in stroke. Recent research has shown that PBN-related nitrones also have anti-cancer activity in several experimental cancer models and have potential as therapeutics in some cancers. Also in recent observations nitrones have been shown to act synergistically in combination with antioxidants in the prevention of acute acoustic noise induced hearing loss. The mechanistic basis of the potent biological activity of PBN-related nitrones is not known. Even though PBN-related nitrones do decrease oxidative stress and oxidative damage, their potent biological anti-inflammatory activity and their ability to alter cellular signaling processes can not readily be explained by conventional notions of free radical trapping biochemistry. This review is focused on our observations and others where the use of selected nitrones as novel therapeutics have been evaluated in experimental models in the context of free radical biochemical and cellular processes considered important in pathologic conditions and age-related diseases.
PMCID: PMC2796547  PMID: 18793715
Nitrones; Stroke; Glioma; Hepatocellular Carcinoma; Hearing Loss; Acoustical Trauma
24.  Free radical scavenging activities of Cnidium officinale Makino and Ligusticum chuanxiong Hort. methanolic extracts 
Pharmacognosy Magazine  2010;6(24):323-330.
Antioxidants from natural resources possess multifaceted and importance of the activities provides substantial scope in neurodegenerative diseases. The aim of this study was to assess and compare the free radical scavenging activities of Cnidium officinale and Ligusticum chuanxiong, which are closely related species.
Materials and Methods:
The scavenging activities of plant materials were evaluated using Trolox equivalent antioxidant capacity (TEAC), oxygen radical absorbance capacity (ORAC) and 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide radical (O2·-), hydrogen peroxide (H2O2), hydroxyl (OH·), nitric oxide radical (NO·) and metal chelation. In addition, the cell viability and nitric oxide release were assayed using Neuro-2a (N2a) cells.
The methanolic extracts of C. officinale and L. chuanxiong showed scavenging activities of free radicals with an additional antioxidant capacity. Moreover, the efficacy on the cell viability and nitric oxide release in cell culture model has been established.
Results of the present study suggests that the extracts of C. officinale and L. chuanxiong have comparatively similar free radical scavenging activities in vitro and may have important health effects.
PMCID: PMC2992148  PMID: 21120037
Antioxidant; Cnidium officinale; free radical scavenging; Ligusticum chuanxiong; Umbelliferae
25.  Estrogen Regulation of Mitochondrial Bioenergetics: Implications for Prevention of Alzheimer’s Disease 
Alzheimer’s disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid.
Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance.
Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The “healthy cell bias of estrogen action” hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.
PMCID: PMC3970844  PMID: 22840752

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