TY - JOUR
T1 - γ-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Aβ(1-42)-mediated oxidative stress and neurotoxicity
T2 - Implications for Alzheimer's disease
AU - Boyd-Kimball, Debra
AU - Sultana, Rukhsana
AU - Mohmmad Abdul, Hafiz
AU - Butterfield, D. Allan
PY - 2005/3/1
Y1 - 2005/3/1
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. Aβ(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 γ-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 Aβ(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 γ-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 Aβ(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 Aβ(1-42) in AD brain.
AB - 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. Aβ(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 γ-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 Aβ(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 γ-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 Aβ(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 Aβ(1-42) in AD brain.
KW - Alzheimer's disease
KW - Amyloid beta peptide
KW - Glutathione
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U2 - 10.1002/jnr.20394
DO - 10.1002/jnr.20394
M3 - Article
C2 - 15678514
AN - SCOPUS:16444379174
SN - 0360-4012
VL - 79
SP - 700
EP - 706
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
IS - 5
ER -