Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients

Perry, Thomas L.; Yong, V. Wee

doi:10.1016/0304-3940(86)90320-4

Cited by 342 publications

(176 citation statements)

References 18 publications

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“…1B). Treatment with 40 μg/ml dox for 24 h resulted in a decrease in GSH levels of approximately 50%, a similar decrease to that previously reported to occur in the SN of early PD brains [2,5]. Consequently, this dosage regime was used for all subsequent experiments.…”

Section: Generation Of N27 Anti-gcl Cells With Inducibly Reduced Gcl supporting

confidence: 68%

“…Depletion in levels of the thiol reducing agent glutathione (GSH) is one of the earliest reported biochemical events to occur in the affected substantia nigra (SN) of PD patients [1]; decreases in total glutathione (GSH + GSSG) levels appears to occur prior to the selective loss of mitochondrial complex I (CI) activity associated with the disease which is believed to contribute to subsequent dopaminergic cell death. GSH depletion is not observed in any other neurodegenerative disorders of the basal ganglia but is unique to PD [2,3]. GSH is synthesized by a two-step reaction involving the enzymes γ-glutamylcysteine ligase (GCL) and glutathione synthetase (GS).…”

Section: Introductionmentioning

confidence: 99%

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Up-regulation of γ-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson's disease

Chinta¹,

Kumar²,

Zhang³

et al. 2006

Free Radical Biology and Medicine

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Up-regulation of activity of γ-glutamyl transpeptidase (GGT) has been reported to occur in the Parkinsonian substantia nigra, the area of the brain affected by the disease. Increased GGT activity has been hypothesized to play a role in subsequent mitochondrial complex I (CI) inhibition by increasing cysteine as substrate for cellular uptake. Intracellular cysteine has been proposed to form toxic adducts with dopamine which can be metabolized to compounds which inhibit CI activity. We have demonstrated that in addition to CI inhibition, GGT activity is up-regulated in dopaminergic cells as a consequence of glutathione depletion. Inhibition of GGT rather than resulting in increased CI inhibition results in exacerbation of this inhibitory effect. This suggests that increased GGT activity is likely an adaptive response to the loss of glutathione to conserve intracellular glutathione content and results in a compensatory effect on CI activity rather than in its inhibition as has been previously widely hypothesized.

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Section: Generation Of N27 Anti-gcl Cells With Inducibly Reduced Gcl supporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Up-regulation of γ-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson's disease

Chinta¹,

Kumar²,

Zhang³

et al. 2006

Free Radical Biology and Medicine

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“…Both oxidative stress and electrophilic quinone molecules have been implicated in destruction of dopaminergic neurons in the substantia nigra in PD (Munch et al, 1998). Studies over the past decade have demonstrated that a variety of cellular antioxidants and phase 2 enzymes, especially GSH and NQO1 can protect neuronal cells against oxidative and electrophilic insults (Perry and Yong, 1986;Siegel et al, 1997). In this context, the coordinated induction of endogenous GSH and NQO1 via the use of chemoprotective agents appears to be a promising strategy for protecting against the oxidative/ electrophilic pathophysiological processes underlying PD.…”

Section: Discussionmentioning

confidence: 99%

“…GSH is also the co-substrate for several key cellular antioxidative and phase 2 enzymes. In this context, early depletion of cellular GSH and the accompanying oxidative stress in substantia nigra are important biochemical features of PD (Perry et al, 1982;Perry and Yong, 1986;Sofic et al, 1992;Spencer et al, 1995;Sechi et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

et al. 2008

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Evidence suggests oxidative and electrophilic stress as a major factor contributing to the neuronal cell death in neurodegenerative disorders, especially Parkinson's disease. Consistent with this concept, administration of exogenous antioxidants has been shown to be protective against oxidative/ electrophilic neurodegeneration. However, whether induction of endogenous antioxidants and phase 2 enzymes by the unique chemoprotectant, 3H-1,2-dithiole-3-thione (D3T) in neuronal cells also affords protection against oxidative and electrophilic neurocytotoxicity has not been carefully investigated. In this study, we showed that incubation of SH-SY5Y neuroblastoma cells or primary human neurons with micromolar concentrations (10-100 μM) of D3T for 24 h resulted in significant increases in the levels of reduced glutathione (GSH) and NAD(P)H:quinone oxidoreductase 1 (NQO1), two crucial cellular defenses against oxidative and electrophilic stress. D3T treatment also caused increases in mRNA expression of γ-glutamylcysteine ligase catalytic subunit and NQO1 in SH-SY5Y cells. In addition, D3T treatment of the neuronal cells also resulted in a marked elevation of GSH content in the mitochondrial compartment. To determine the protective effects of the D3T-induced cellular defenses on neurotoxicant-elicited cell injury, SH-SY5Y cells were pretreated with D3T for 24 h and then exposed to dopamine, 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), or H 2 O 2 , agents that are known to be involved in neuron degeneration. We observed that D3T-pretreatment of SH-SY5Y cells led to significant protection against the cytotoxicity elicited by the above neurotoxicants. Similar neurocytoprotective effects of D3T-pretreatment were also observed in primary human neurons exposed to 6-OHDA or HNE. Taken together, this study demonstrates that D3T potently induces neuronal cellular GSH and NQO1 as well as mitochondrial GSH, and that such upregulated endogenous defenses are accompanied by increased resistance to oxidative and electrophilic neurocytotoxicity.

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“…Evidence for oxidative stress occurring in Parkinson's disease has come from studies that show a decrease (up to 40%) in levels of the cellular antioxidant, glutathione (GSH) [4][5][6][7]. GSH protects cells from oxidant damage [8,9] and has been shown to reduce levels of reactive free radicals, including semiquinones and the hydroxyl radical.…”

Section: Introductionmentioning

confidence: 99%

Depletion of glutathione does not affect electron transport chain complex activity in brain mitochondria: Implications for Parkinson disease and postmortem studies

Heales

Menzes

Davey

2011

Free Radical Biology and Medicine

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Glutathione is an important antioxidant in the brain that appears to be decreased, in conjunction with mitochondrial complex I activity, in Parkinson's disease patients. In postmortem analysis, measurement of glutathione levels and complex I activity can be delayed up to 20 h. We investigated if depletion of glutathione in the pre-weanling rat induces a reduction in complex I activity in brain mitochondria and the effect that postmortem delay has on glutathione levels and electron transport chain activities.Following injection with the gamma-glutamyl cysteine ligase inhibitor, buthionine sulfoximine (L-BSO), glutathione levels were decreased by 53% compared to the control values in whole brain homogenates. During postmortem delay of 24 hours, in which animals were kept at 4˚C, levels of glutathione decreased in the control group by 58% and in the L-BSO treated group by 79%. However, during this period, there were no changes in mitochondrial electron transport chain complex I, II-III and IV activities in either group. These results suggest that a pre-existing deficiency of glutathione or a loss of glutathione during postmortem delay does not influence mitochondrial respiratory chain activities in the brain.

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Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients

Cited by 342 publications

References 18 publications

Up-regulation of γ-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson's disease

Up-regulation of γ-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson's disease

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

Depletion of glutathione does not affect electron transport chain complex activity in brain mitochondria: Implications for Parkinson disease and postmortem studies

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