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Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1-42)-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease.
J Neurosci Res 2005; 79(5):700-6JN

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. 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.

Authors+Show Affiliations

Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15678514

Citation

Boyd-Kimball, Debra, et al. "Gamma-glutamylcysteine Ethyl Ester-induced Up-regulation of Glutathione Protects Neurons Against Abeta(1-42)-mediated Oxidative Stress and Neurotoxicity: Implications for Alzheimer's Disease." Journal of Neuroscience Research, vol. 79, no. 5, 2005, pp. 700-6.
Boyd-Kimball D, Sultana R, Abdul HM, et al. Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1-42)-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. J Neurosci Res. 2005;79(5):700-6.
Boyd-Kimball, D., Sultana, R., Abdul, H. M., & Butterfield, D. A. (2005). Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1-42)-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. Journal of Neuroscience Research, 79(5), pp. 700-6.
Boyd-Kimball D, et al. Gamma-glutamylcysteine Ethyl Ester-induced Up-regulation of Glutathione Protects Neurons Against Abeta(1-42)-mediated Oxidative Stress and Neurotoxicity: Implications for Alzheimer's Disease. J Neurosci Res. 2005 Mar 1;79(5):700-6. PubMed PMID: 15678514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1-42)-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. AU - Boyd-Kimball,Debra, AU - Sultana,Rukhsana, AU - Abdul,Hafiz Mohmmad, AU - Butterfield,D Allan, PY - 2005/1/29/pubmed PY - 2005/5/10/medline PY - 2005/1/29/entrez SP - 700 EP - 6 JF - Journal of neuroscience research JO - J. Neurosci. Res. VL - 79 IS - 5 N2 - 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. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/15678514/Gamma_glutamylcysteine_ethyl_ester_induced_up_regulation_of_glutathione_protects_neurons_against_Abeta_1_42__mediated_oxidative_stress_and_neurotoxicity:_implications_for_Alzheimer's_disease_ L2 - https://doi.org/10.1002/jnr.20394 DB - PRIME DP - Unbound Medicine ER -