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Oxidative Stress Clinical Studies

  1. Neurodegenerative diseases and oxidative stress

    Kevin J Barnham, Colin L. Masters and Ashley I Bush.
    Nature Reviews Drug Discovery 3, 205-214 (2004)

    Abstract
    Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

  2. Gamma-Glutamylcysteine Ethyl Ester-Induced Up-Regulation of Glutathione Protects Neurons Against Aß (1-42)-Mediated Oxidative Stress and Neurotoxicity: Implications for Alzheimer's Disease

    Debra Boyd-Kimball, Rukhsana Sultana, Hafz Mohmmad Abdul and D. Allan Butterfield
    Journal of Neuroscience Research 79:700-706 (2005)

    Abstract
    Glutathione (GSH) is an important endogenous antioxidant found in millimolar concentrations in the brain. GSH levels have been shown to decrease with aging. Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging and oxidative stress. Aß (1- 42) has been shown to induce oxidative stress and has been proposed to play a central role in the oxidative damage detected in AD brain. It has been shown that administration of Gamma-glutamylcysteine ethyl ester (GCEE) increases cellular levels of GSH, circumventing the regulation of GSH biosynthesis by providing the limiting substrate. In this study, we evaluated the protective role of up-regulation of GSH by GCEE against the oxidative and neurotoxic effects of Aß(1- 42) in primary neuronal culture. Addition of GCEE to neurons led to an elevated mean cellular GSH level compared with untreated control. Inhibition of ?-glutamylcysteine synthetase by buthionine sulfoximine (BSO) led to a 98% decrease in total cellular GSH compared with control, which was returned to control levels by addition of GCEE. Taken together, these results suggest that GCEE up-regulates cellular GSH levels which, in turn, protects neurons against protein oxidation, loss of mitochondrial function, and DNA fragmentation induced by Aß(1- 42). These results are consistent with the notion that up-regulation of GSH by GCEE may play a viable protective role in the oxidative and neurotoxicity induced by Aß(1- 42) in AD brain.

  3. Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease

    Ilaria Guidi, Daniela Galimberti, Silvia Lonati, Cristina Novembrino, Fabrizia Bamonti, Marco Tiriticco, Chiara Fenoglio, Eliana Venturelli, Pierluigi Baron, Nereo Bresolin, Elio Scarpini
    Neurobiology of Aging. 2006;27(2) 262-269.

    Abstract
    Increasing evidence supports a role of oxidative imbalance, characterized by impaired antioxidant enzymatic activity and increased reactive oxygen species (ROS) production, in mild cognitive impairment (MCI) and Alzheimer's disease (AD) pathogenesis. Hyperhomocysteinemia, another risk factor for AD, also contributes to oxidative damage. Plasma total homocysteine (tHcy) and ROS levels, and total antioxidant capacity (TAC) were determined in 71 AD, 36 MCI and 28 vascular dementia (VaD) patients as well as in 44 age-matched controls. tHcy levels were significantly increased in patients with AD and VaD an a trend towards an increase in multiple domain MCI was observed. TAC was significantly decreased in AD as well as MCI, but not in VaD patients. In AD patients, a negative correlation was found between TAC and disease duration. ROS levels did not differ among groups, but were correlated with age. In conclusion, a pattern characterized by increased tHcy levels and decreased TAC is present in AD as well as MCI patients. While increased tHcy levels were also found in VaD, TAC modifications occur specifically in AD. ROS levels appear to be correlated with age rather than with a specific dementing disorder, thus leading to the hypothesis that oxidative imbalance observed in AD could be due to a decreased TAC.

  4. Homocysteine potentiates b-amyloid neurotoxicity: role of oxidative stress

    Pei I. Ho, Scott C. Collins, Sirikarnt Dhitavat, Daniela Ortiz, David Ashline, Eugene Rogers and Thomas B. Shea
    Journal of Neurochemistry, 2001, 78, 249-253

    Abstract
    The cause of neuronal degeneration in Alzheimer's disease (AD) has not been completely clarified, but has been variously attributed to increases in cytosolic calcium and increased generation of reactive oxygen species (ROS). The ß-amyloid fragment (Aß) of the amyloid precursor protein induces calcium influx, ROS and apoptosis. Homocysteine (HC), a neurotoxic amino acid that accumulates in neurological disorders including AD, also induces calcium influx and oxidative stress, which has been shown to enhance neuronal excitotoxicity, leading to apoptosis. We examined the possibility that HC may augment Aß neurotoxicity. HC potentiated the Aß-induced increase in cytosolic calcium and apoptosis in differentiated SH-SY-5Y human neuroblastoma cells. The antioxidant vitamin E and the glutathione precursor N-acetyl-L-cysteine blocked apoptosis following co-treatment with HC and Aß, indicating that apoptosis is associated with oxidative stress. These findings underscore that moderate accumulation of excitotoxins at concentrations that alone do not appear to initiate adverse events may enhance the effects of other factors known to cause neurodegeneration such as Aß.

  5. Evidence of increased oxidative damage in subjects with mild cognitive impairment

    JN Keller, FA Schmitt, SW Scheff, Q Ding, Q Chen, DA Butterfield and WR Markesbery
    Neurology 2005;64:1152-1156.

    Abstract
    Objective: To determine if increased levels of oxidative damage are present in the brains of persons with mild cognitive impairment (MCI), a condition that often precedes Alzheimer disease (AD).

    Methods: The authors assessed the amount of protein carbonyls, thiobarbituric acid-reactive substances (TBARS), and malondialdehyde in the superior and middle temporal gyri (SMTG) and cerebellum of short postmortem interval and longitudinally evaluated normal subjects and those with MCI and early AD.

    Results: Elevated levels of protein carbonyls (~25%), malondialdehyde (~60%), and TBARS (~210%) were observed in the SMTG of individuals with MCI and early AD vs. normal control subjects. The elevation in TBARS was associated with the numbers of neuritic but no diffuse plaques. Levels of protein carbonyls increased as delayed verbal memory performance declined.

    Conclusion: Oxidative damage occurs in the brain of subjects with mild cognitive impairment, suggesting that oxidative damage may be one of the earliest events in the onset and progression of Alzheimer disease.

  6. Alzheimer's Disease and Total Plasma Aminothiols

    Andrew McCaddon, Peter Hudson, Diane Hill, Joan Barber, Alwyn Lloyd, Gareth Davies, and Björn Regland
    Biol Psychiatry. 2003; 53:254-260


    This graph represents technical information presented in McCaddon et al. Alzheimer's disease and plasma aminothiols. Biol Psychiatry. 2003; 53:254-260

    Abstract
    Background: Plasma homocysteine is elevated in Alzheimer's disease, but little is known regarding levels of related aminothiols in the disease. We therefore determined total plasma homocysteine, cysteine, and glutathione levels in patients and control subjects and investigated their relationship with cognitive scores.

    Methods: We performed a prospective, case-controlled survey based in two UK Psychogeriatric Assessment Centres. Fifty patients with features compatible with DSM-IV criteria for primary degenerative dementia of Alzheimer type were recruited together with 57 cognitively intact age- and gender-matched control subjects. Mini-Mental State and Alzheimer's Disease Assessment Scale-Cognitive Subsection (ADAS-Cog) scores were determined for patients and control subjects. Aminothiols were assayed with an automated high-performance liquid chromatography (HPLC) system.

    Results: Patients had significantly elevated total plasma homocysteine (p _ .001) and cysteine (p _ .01), but there were no group differences for total plasma glutathione. Glutathione was, however, a highly significant and independent predictor of cognitive scores in patients (p _002); lower plasma levels were associated with more severe cognitive impairment.

    Conclusions: Total plasma homocysteine and cysteine are elevated in Alzheimer's disease, suggesting intact transulphuration but defective remethylation of homocysteine in the disease. Total plasma glutathione levels in patients correlate with cognitive scores. Taken together, these observations perhaps reflect the differential effects of Alzheimer's disease-related oxidative stress on the two key pathways of homocysteine metabolism.

  7. In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain

    C.B. Pocernich M. La Fontaine D.A. Butterfield
    Neurochemistry International 36 (2000) 185-191 www.elsevier.com/locate/neuint

    Abstract
    Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2- treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.