Glutathione, oxidative stress and neurodegeneration

Schulz, Jörg B.; Lindenau, Jörg; Seyfried, Jan; Dichgans, J.

doi:10.1046/j.1432-1327.2000.01595.x

Cited by 1,045 publications

(673 citation statements)

References 73 publications

(80 reference statements)

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“…There is significant evidence of disturbance of GSH homeostasis that either leads to or results from oxidative stress in neurodegenerative disorders [28]. The decline in GSH levels in this study can be explained as a consequence of increased demands on the GSH system in schizophrenia.…”

Section: Discussionmentioning

confidence: 55%

Oxidative Stress-Induced Response of Some Endogenous Antioxidants in Schizophrenia

Dadheech

Sharma

2012

Ind J Clin Biochem

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Section: Discussionmentioning

confidence: 55%

Oxidative Stress-Induced Response of Some Endogenous Antioxidants in Schizophrenia

Dadheech

Sharma

2012

Ind J Clin Biochem

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“…Moreover, these effects are also prevented by GSH (Figs. 1-4) which, besides several cellular functions [47,48], plays a pivotal role in the regulation of apoptosis [49], inhibiting the VP-16-induced apoptosis [7]. Similar inhibitor effects on these mitochondrial events are caused by the thiol protecting agent DTT (Figs.…”

Section: Discussionmentioning

confidence: 93%

Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis

Custódio

Cardoso

Almeida

2002

Chemico-Biological Interactions

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Etoposide (VP-16) is known to promote cell apoptosis either in cancer or in normal cells as a side effect. This fact is preceded by the induction of several mitochondrial events, including increase in Bax/Bcl-2 ratio followed by cytochrome c release and consequent activation of caspase-9 and -3, reduction of ATP levels, depolarization of membrane potential (Dc) and rupture of the outer membrane. These events are apoptotic factors essentially associated with the induction of the mitochondrial permeability transition (MPT). VP-16 has been shown to stimulate the Ca 2 + -dependent MPT induction similarly to prooxidants and to promote apoptosis by oxidative stress mechanisms, which is prevented by glutathione (GSH) and N-acetylcysteine (NAC). Therefore, the aim of this work was to study the effects of antioxidants and thiol protecting agents on MPT promoted by VP-16, (2002) 169-184 170 attempting to identify the underlying mechanisms on VP-16-induced apoptosis. The increased sensitivity of isolated mitochondria to Ca 2 + -induced swelling, Ca 2 + release, depolarization of Dc and uncoupling of respiration promoted by VP-16, which are prevented by cyclosporine A proving that VP-16 induces the MPT, are also efficiently prevented by ascorbate, the primary reductant of the phenoxyl radicals produced by VP-16. The thiol reagents GSH, dithiothreitol and N-ethylmaleimide, which have been reported to prevent the MPT induction, also protect this event promoted by VP-16. The inhibition of the VP-16-induced MPT by antioxidants agrees with the prevention of etoposide-induced apoptosis by GSH and NAC and suggests the generation of oxidant species as a potential mechanism underlying the MPT that may trigger the release of mitochondrial apoptogenic factors responsible for apoptotic cascade activation.

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“…Glutathione is widely recognized as an endogenous nonenzymatic antioxidant, an oxyradical scavenger, thereby useful in protecting against oxidative damage by free radicals and inhibiting lipid peroxidation and DNA damage [29][30][31][32][33]. Glutathione has been implicated in a wide range of metabolic processes, including cell division, DNA repair, regulation of enzyme activity, activation of transcription factors, modulation of anion and cation homeostasis and protection against oxidative damage [34].…”

Section: Introductionmentioning

confidence: 99%

In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

Ansari

Joshi

Huang

et al. 2006

Free Radical Biology and Medicine

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Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH), has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, Aβ (1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro-and anti-apoptotic factor proteins. The present study was undertaken to test the hypothesis that i.p. injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils 1 h post injection intraperitonially (i.p.) with D609 and subsequently treated in vitro with the oxidants Fe 2+ /H 2 O 2 (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals) and AD-relevant amyloid β-peptide 1-42 [Aβ (1-42)]. Brain mitochondria isolated from the gerbils previously injected i.p. with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3-NT), and cytochrome-c release compared to oxidant-treated brain mitochondria isolated from salineinjected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione-S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GR) in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These anti-apoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD.

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Glutathione, oxidative stress and neurodegeneration

Cited by 1,045 publications

References 73 publications

Oxidative Stress-Induced Response of Some Endogenous Antioxidants in Schizophrenia

Oxidative Stress-Induced Response of Some Endogenous Antioxidants in Schizophrenia

Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis

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