?-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against A?(1-42)-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 03/2005; 79(5):700-6. DOI: 10.1002/jnr.20394
Source: PubMed


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. Abeta(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 Abeta(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 gamma-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 Abeta(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 Abeta(1-42) in AD brain.

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    • "Several recent studies using glutathione or glutathione inducers (such as γ-glutamylcysteine ethyl ester, glutathione-ethyl-ester, N-acetyl-l-cysteine choline) and AD cell lines or primary neurons expressing mutant APP demonstrated that increased glutathione levels protect neurons against protein oxidation, loss of mitochondrial function, and DNA fragmentation induced by Aβ (Pocernich et al. 2001; Boyd-Kimball et al. 2005a, b; Abe et al. 2004). These mitochondrially targeted antioxidants preferentially enter the mitochondria where they neutralize free radicals and decrease oxidative damage, and may protect neurons. "
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    ABSTRACT: Mitochondria are key cytoplasmic organelles, responsible for generating cellular energy, regulating intracellular calcium levels, altering the reduction-oxidation potential of cells, and regulating cell death. Increasing evidence suggests that mitochondria play a central role in aging and in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Freidriech ataxia. Further, several lines of evidence suggest that mitochondrial dysfunction is an early event in most late-onset neurodegenerative diseases. Biochemical and animal model studies of inherited neurodegenerative diseases have revealed that mutant proteins of these diseases are associated with mitochondria. Mutant proteins are reported to block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins and disrupt the electron transport chain, induce free radicals, cause mitochondrial dysfunction, and, ultimately, damage neurons. This article discusses critical issues of mitochondria causing dysfunction in aging and neurodegenerative diseases, and discusses the potential of developing mitochondrial medicine, particularly mitochondrially targeted antioxidants, to treat aging and neurodegenerative diseases.
    Neuromolecular medicine 07/2008; 10(4):291-315. DOI:10.1007/s12017-008-8044-z · 3.68 Impact Factor
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    • "This would suggest that GSH is metabolized to cysteinylglycine and glutamate in the bloodstream. Cysteineylglycine may serve as a substrate for GSH biosynthesis (Anderson et al. 1985;Boyd-Kimball et al. 2005), but whether it crosses the BBB is unknown. The restriction of the BBB to small peptides, however, makes the uptake of cysteinylglycine unlikely (Cornford et al. 1978). "
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    ABSTRACT: Parkinson's disease (PD) is associated with loss of total glutathione (GSH) which may contribute to progressive cell death. Peripheral GSH administration has been used clinically with reported benefits. Despite this, there is little specific information to characterize its cellular uptake or clearance, brain elevation with peripheral delivery or neuroprotective efficacy in PD models. The current study was carried out to provide this information using in vitro and in vivo approaches. In rat mesencephalic culture, the monoethyl ester of GSH (GEE), but not GSH (1-10 mM, 24 h) produced a dose-dependent elevation in GSH. The half-life for clearance was 10.14 h and was not different in cells depleted of GSH prior to loading. Elevation of GSH with GEE protected neurons from oxidative stress with H2O2 or metabolic stress with the complex I and II inhibitors MPP+ and malonate, respectively. To determine if peripheral administration of GEE could elevate brain GSH levels, rats were administered 0.1-50 mg/kg/day GEE via osmotic minipump either subcutaneously (sc) or via a cannula placed into the left cerebral ventricle (icv) for 28 days. Only central delivery of GEE resulted in significant elevations of brain GSH. Elevation of brain GSH by icv infusion of GEE was examined for its neuroprotective effects against chronic central delivery of MPP+. Infusion of 0.142 mg/kg/day MPP+ for 28 days caused a selective ipsilateral loss of striatal dopamine. Co-infusion of MPP+ with 10 mg/kg/day GEE significantly protected against striatal dopamine loss. These findings show that the ethyl ester of GSH but not GSH per se can elevate intracellular GSH, that brain elevation of GSH requires central delivery of the ethyl ester and that this elevation provides neuroprotection against oxidative stress or chronic mitochondrial impairment.
    Experimental Neurology 03/2007; 203(2):512-20. DOI:10.1016/j.expneurol.2006.09.004 · 4.70 Impact Factor
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    • "Pyruvate kinase, GAPDH, and malate dehydrogenase are all glycolytic enzymes involved in the production of ATP. These enzymes have been shown to be oxidatively modified in other aging or AD-related models (Boyd-Kimball et al., 2005a; Lovell et al., 2005; Poon et al., 2005). Pyruvate kinase catalyzes the final step in glycolysis forming ATP from ADP when converting phosphoenolpyruvate to pyruvate. "
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    ABSTRACT: Oxidative stress has been implicated in the pathophysiology of a number of diseases, including neurodegenerative disorders such as Alzheimer's disease (AD), a neurodegenerative disorder associated with cognitive decline and enhanced oxidative stress. Amyloid-beta peptide(1-42) (Abeta(1-42)), one of the main component of senile plaques, can induce in vitro and in vivo oxidative damage to neuronal cells through its ability to produce free radicals. The aim of this study was to investigate the protective effect of the xanthate D609 on Abeta(1-42)-induced protein oxidation by using a redox proteomics approach. D609 was recently found to be a free radical scavenger and antioxidant. In the present study, rat primary neuronal cells were pretreated with 50 microM of D609, followed by incubation with 10 microM Abeta(1-42) for 24 hr. In the cells treated with Abeta(1-42) alone, four proteins that were significantly oxidized were identified: glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, malate dehydrogenase, and 14-3-3 zeta. Pretreatment of neuronal cultures with D609 prior to Abeta(1-42) protected all the identified oxidized proteins in the present study against Abeta(1-42)-mediated protein oxidation. Therefore, D609 may ameliorate the Abeta(1-42)-induced oxidative modification. We discuss the implications of these Abeta(1-42)-mediated oxidatively modified proteins for AD pathology and for potential therapeutic intervention in this dementing disorder.
    Journal of Neuroscience Research 08/2006; 84(2):409-17. DOI:10.1002/jnr.20876 · 2.59 Impact Factor
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