Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D00031 (Glutathione)
5,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured amino acid contents in autopsied brains of seven patients with progressive supranuclear palsy (PSP) and in control subjects dying without brain disease. Glutathione was also quantitated in rapidly frozen brains of PSP patients, Parkinson's disease (PD) patients, and controls. In PSP, we found glutamic acid markedly increased in the nucleus accumbens; taurine significantly increased in nucleus accumbens, substantia nigra, and globus pallidus; and gamma-aminobutyric acid significantly increased in nucleus accumbens and putamen. Glycerophosphoethanolamine contents were significantly increased in most regions. Glutathione, which is significantly decreased in substantia nigra in PD, was increased in this brain region in PSP, suggesting that different mechanisms may be responsible for destruction of dopaminergic nigrostriatal neurons in these two disorders.
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PMID:Brain amino acids and glutathione in progressive supranuclear palsy. 336 77

Glutathione levels are decreased in the substantia nigra of patients with Parkinson's disease. We studied whether glutathione depletion contributes to dopaminergic cell death using a specific inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (BSO). We found no significant reduction of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta (SNpc) when BSO was administered systemically to preweanling mice or locally to the SNpc of adult rats. However, the combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in preweanling mice and the combination of nigral injections of BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridinium), the active metabolite of MPTP in adult rats, potentiated the toxic effects of MPTP and MPP+ on nigral neurones. Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.
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PMID:Glutathione depletion potentiates MPTP and MPP+ toxicity in nigral dopaminergic neurones. 872 74

Reactive oxygen species are believed to play a crucial role in situations where dopamine neurons die, such as in Parkinson's disease or during intracerebral transplantation of embryonic mesencephalic tissue. The present study was designed to address the question whether, and to what extent, the glutathione redox system is important for the viability of rat embryonic dopamine neurons in vitro. Furthermore, we studied whether the lazaroid U-83836E, a 2-methylaminochroman that inhibits lipid peroxidation, affects the survival of cultured mesencephalic neurons subjected to experimentally induced glutathione depletion. Glutathione depletion was achieved by exposing dissociated mesencephalic cell cultures to L-buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, at four different concentrations (1, 10,100, and 1,000 microM). Dopamine neuron survival was significantly reduced by 65-94% in a concentration-dependent manner by 10-1,000 microM BSO. The neurotoxic effects of BSO were almost completely prevented by supplementing the culture medium with 0.3 microM U-83836E. As assessed by HPLC analysis, BSO treatment was associated with a marked reduction of cellular glutathione content, and this depletion was not altered by the presence of U-83836E. We conclude that in the present insult model of severe glutathione depletion, the lazaroid can afford efficient neuroprotection that does not seem to be mediated by a direct interaction with BSO or glutathione, but rather via an independent pathway.
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PMID:Lazaroid treatment prevents death of cultured rat embryonic mesencephalic neurons following glutathione depletion. 885 50

o-Quinones are physiological oxidation products of catecholamines that contribute to redox cycling, toxicity and apoptosis, i.e. the neurodegenerative processes underlying Parkinson's disease and schizophrenia. The present study shows that the cyclized o-quinones aminochrome, dopachrome, adrenochrome and noradrenochrome, derived from dopamine, dopa, adrenaline and noradrenaline respectively, are efficiently conjugated with glutathione in the presence of human glutathione transferase (GST) M2-2. The oxidation product of adrenaline, adrenochrome, is less active as a substrate for GST M2-2, and more efficiently conjugated by GST M1-1. Evidence for expression of GST M2-2 in substantia nigra of human brain was obtained by identification of the corresponding PCR product in a cDNA library. Glutathione conjugation of these quinones is a detoxication reaction that prevents redox cycling, thus indicating that GSTs have a cytoprotective role involving elimination of reactive chemical species originating from the oxidative metabolism of catecholamines. In particular, GST M2-2 has the capacity to provide protection relevant to the prevention of neurodegenerative diseases.
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PMID:Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. 916 36

Oxidative stress is believed to play important roles in neuronal cell death associated with many different neurodegenerative conditions (e.g., Alzheimer's disease, Parkinson's disease, and cerebral ischemia), and it is believed also that apoptosis is an important mode of cell death in these disorders. Membrane lipid peroxidation has been documented in the brain regions affected in these disorders as well as in cell culture and in vivo models. We now provide evidence that 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, is a key mediator of neuronal apoptosis induced by oxidative stress. HNE induced apoptosis in PC12 cells and primary rat hippocampal neurons. Oxidative insults (FeSO4 and amyloid beta-peptide) induced lipid peroxidation, cellular accumulation of HNE, and apoptosis. Bcl-2 prevented apoptosis of PC12 cells induced by oxidative stress and HNE. Antioxidants that suppress lipid peroxidation protected against apoptosis induced by oxidative insults, but not that induced by HNE. Glutathione, which binds HNE, protected neurons against apoptosis induced by oxidative stress and HNE. PC12 cells expressing Bcl-2 exhibited higher levels of glutathione and lower levels of HNE after oxidative stress. Collectively, the data identify that HNE is a novel nonprotein mediator of oxidative stress-induced neuronal apoptosis and suggest that the antiapoptotic action of glutathione may involve detoxification of HNE.
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PMID:Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. 918 46

Neuronal damage in certain cellular populations in the brain has been linked to oxidative stress accompanied by an elevation in intracellular calcium. Many questions remain about how such oxidative stress occurs and how it affects calcium homeostasis. Glutathione (GSH) is a major regulator of cellular redox status in the brain, and lowered GSH levels have been associated with dopaminergic cell loss in Parkinson's disease (PD). We found that transfection of antisense oligomers directed against glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, into PC12 cells resulted in decreased GSH and increased levels of ROS. Decreased GSH levels also correlated with an increase in intracellular calcium levels. Data from this study suggest that dopaminergic neurons are very sensitive to decreases in the internal oxidant buffering capacity of the cell caused by reductions in GSH levels, and that alterations in this parameter can result in disruption of calcium homeostasis and cell death. These results may be of particular significance for therapeutic treatment of PD, as those dopaminergic neurons that are spared in this disorder appear to contain the calcium binding protein, calbindin.
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PMID:Decreased glutathione results in calcium-mediated cell death in PC12. 935 49

Glutathione depletion occurs in several forms of apoptosis and is associated with Parkinson's disease and HIV toxicity. The neurotransmitter glutamate kills immature cortical neurons and a hippocampal nerve cell line via an oxidative pathway associated with glutathione depletion. It is shown here that soluble guanylyl cyclase (sGC) activity is required for nerve cell death caused by glutathione depletion. Inhibitors of sGC block glutamate toxicity and a cGMP analogue potentiates cell death. Glutamate also induces an elevation of cGMP that occurs late in the cell death pathway. The resultant cGMP modulates the increase in intracellular calcium that precedes cell death because sGC inhibitors prevent calcium elevation and the cGMP analogue potentiates the increase in intracellular calcium. These results suggest that the final pathway of glutamate induced nerve cell death is through a cGMP-modulated calcium channel.
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PMID:Requirement for cGMP in nerve cell death caused by glutathione depletion. 938 76

Oxidative stress is thought to play an important role in the pathogenesis of Parkinson's disease (PD). Glutathione (GSH), a major cellular antioxidant, is decreased in the substantia nigra pars compacta of PD patients. The aim of the present study was to investigate whether deprenyl and its desmethyl metabolite, putative neuroprotective agents in the treatment of PD, could protect cultured rat mesencephalic neurons from cell death caused by GSH depletion due to treatment with L-buthionine-(S,R)-sulfoximine (BSO). BSO (10 microM) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium. Both deprenyl and desmethylselegiline, at concentrations of 5 and 50 microM, significantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoamine oxidase type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of deprenyl. Protection was not associated with inhibition of dopamine uptake by deprenyl because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The antioxidant ascorbic acid (200 microM) also protected against BSO-induced cell death, suggesting that oxidative events were involved. This study demonstrates that deprenyl and its desmethyl metabolite can diminish cell death associated with GSH depletion.
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PMID:Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion. 945 17

Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2-treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.
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PMID:In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain. 1067 51

Altered glial cell function occurring in substantia nigra in Parkinson' disease may lead to the release of cytokines and impairment of neurotrophic factor production, which in turn, may cause dopaminergic apoptosis. To evaluate this concept, primary cultures of rat brain astrocytes were activated with lipopolysaccharide (LPS), depleted of glutathione with L-buthionine-[S,R]-sulfoximine or subjected to complex I inhibition with 1-methyl-4-phenylpyridinium. The effects on tumour necrosis factor-alpha (TNF-alpha) release, dopamine-stimulated glial cell line derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) release were determined. LPS activation or inhibition complex I activity, but not glutathione depletion, stimulated TNF-alpha release. Glutathione depletion or complex I inhibition, but not LPS-induced activation, impaired dopamine-stimulated GDNF release. None of these treatments altered BDNF release. Thus, altered glial function leading to TNF-alpha-mediated or GDNF withdrawal-induced dopaminergic apoptosis may contribute to nigral degeneration in Parkinson's disease.
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PMID:Dysfunction of rat forebrain astrocytes in culture alters cytokine and neurotrophic factor release. 1078 8


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