Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione (GSH) is considered one of the primary antioxidant compounds in the brain, important for the removal of peroxides from this organ. GSH levels have been reported to be significantly lower in the substantia nigra (SN) of Parkinson patients vs. age-matched controls. Curiously, GSH has been proposed to be present in brain astrocytes rather than in neurons even though these cells are not lost in Parkinson disease. We report that the catalytic and regulatory subunit proteins of glutamyl cysteine synthetase (GCS), the primary enzyme involved in GSH synthesis, are present not only in astrocytes but also in dopaminergic neurons of the SN. This may have important implications in terms of GSH loss associated with Parkinson disease.
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PMID:Glutamyl cysteine synthetase catalytic and regulatory subunits localize to dopaminergic nigral neurons as well as to astrocytes. 1128 48

Compromised mitochondrial energy metabolism and oxidative stress have been associated with the pathophysiology of Parkinson's disease. Our previous experiments exemplified the importance of GSH in the protection of neurons exposed to malonate, a reversible inhibitor of mitochondrial succinate dehydrogenase/complex II. This study further defines the role of oxidative stress during energy inhibition and begins to unravel the mechanisms by which GSH and other antioxidants may contribute to cell survival. Treatment of mesencephalic cultures with 10 microM buthionine sulfoximine for 24 h depleted total GSH by 60%, whereas 3 h exposure to 5 mM 3-amino-1,2,4-triazole irreversibly inactivated catalase activity by 90%. Treatment of GSH-depleted cells with malonate (40 mM) for 6, 12 or 24 h both potentiated and accelerated the time course of malonate toxicity, however, inhibition of catalase had no effect. In contrast, concomitant treatment with buthionine sulfoximine plus 3-amino-1,2,4-triazole in the presence of malonate significantly potentiated toxicity over that observed with malonate plus either inhibitor alone. Consistent with these findings, GSH depletion enhanced malonate-induced reactive oxygen species generation prior to the onset of toxicity. These findings demonstrate that early generation of reactive oxygen species during mitochondrial inhibition contributes to cell damage and that GSH serves as a first line of defense in its removal. Pre-treatment of cultures with 400 microM ascorbate protected completely against malonate toxicity (50 mM, 12 h), whereas treatment with 1 mM Trolox provided partial protection. Protein-GSH mixed disulfide formation during oxidative stress has been suggested to either protect vulnerable protein thiols or conversely to contribute to toxicity. Malonate exposure (50 mM) for 12 h resulted in a modest increase in mixed disulfide formation. However, exposure to the protective combination of ascorbate plus malonate increased membrane bound protein-GSH mixed disulfides three-fold. Mixed disulfide levels returned to baseline by 72 h of recovery indicating the reversible nature of this formation. These results demonstrate an early role for oxidative events during mitochondrial impairment and stress the importance of the glutathione system for removal of reactive oxygen species. Catalase may serve as a secondary defense as the glutathione system becomes limiting. These findings also suggest that protein-GSH mixed disulfide formation under these circumstances may play a protective role.
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PMID:Hydrogen peroxide removal and glutathione mixed disulfide formation during metabolic inhibition in mesencephalic cultures. 1141 33

The principal neuropathological feature of Parkinson's disease is the degeneration of melanized dopamine neurons in the substantia nigra pars compacta (SNc). Characteristic pathobiochemical changes in the parkinsonian SNc include a fall of both dopamine (DA) and glutathione levels (GSH), increased activity of gamma-glutamyl transpeptidase, a key enzyme involved in the degradation of GSH to L-cysteine (CySH), together with evidence for elevated intraneuronal superoxide (O2-*), nitric oxide (NO.) and thence peroxynitrite (ONOO-) generation, and accelerated DA oxidation as indicated by a large rise of the 5-S-cysteinyldopamine (5-S-CyS-DA)/DA concentration ratio. The latter effect is consistent with an increased rate of DA oxidation by O2-* and ONOO- forming DA-o-quinone which reacts with CySH forming 5-S-CyS-DA. However, 5-S-CyS-DA is readily further oxidized to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Previous studies have demonstrated that DHBT-1 is rapidly accumulated by isolated intact rat brain mitochondria and selectively inhibits complex I respiration and the alpha-ketoglutarate dehydrogenase (alpha-KGDH) complex. In this study it is demonstrated that DHBT-1 also inhibits the pyruvate dehydrogenase complex (PDHC). The mechanism underlying the inhibition of all of these enzyme complexes involves bioactivation of intramitochondrial DHBT-1 by oxidation to highly electrophilic metabolites that covalently bind to active site cysteine residues. Thus, oxidative metabolites of intraneuronal 5-S-CyS-DA may contribute to impaired mitochondrial complex I and alpha-KGDH activities known to occur in the parkinsonian SNc and suggest that impaired PDHC evoked by the same metabolites may also occur in PD.
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PMID:Oxidative metabolites of 5-S-cysteinyldopamine inhibit the pyruvate dehydrogenase complex. 1181 Apr 1

Oxidative stress occurs in the brain due to stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, trauma, aging and other conditions. Analysis of the effects of oxidative stress can involve quantitation of brain GSH, GSSG, NADPH and NADP. Reliable and rapid assays have been developed for these compounds and will be presented in detail. The assays have been used to analyze the effects of brain oxidative stress. Thermodynamic calculations can be performed to find the observed electrochemical potentials of the GSSG/GSH and the NADP/NADPH couples during oxidative stress. The biochemical consequences of these thermodynamic changes in the cell will be discussed as well as the defense mechanisms available to the cell to recover from oxidative stress.
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PMID:Brain oxidative stress--analytical chemistry and thermodynamics of glutathione and NADPH. 1189 24

In this study we selected a rat model of Parkinson's disease (PD) by using intrastriatal infusion of the 1-methyl-4-phenyl-pyridinium ion (MPP+) to investigate the neuroprotective action of melatonin and its inhibitory activity on MPP+-impaired glutathione (GSH) system in the nigrostriatal system. Results show that MPP+ caused not only a severe neuronal injury in the striatum and in the ipsilateral substantia nigra (SN), but it also induced a significant decrease in GSH levels and an increase in the GSSG/GSH ratio 3 days after intrastriatal MPP+ infusion. Intraperitoneal co-administration of melatonin (10 mg/kg, five times) significantly attenuated MPP+-induced nigrostriatal neurotoxicity and GSH impairment. Depletion of cytosolic GSH by L-buthionine sulfoximine (BSO) did not cause neuronal damage by itself. It, however, when co-administrated with MPP+, potentiated the GSH reduction in the striatum, without aggravating nigrostriatal neurodegeneration induced by MPP+. Moreover, the MPP+-caused neuronal damage was positively correlated with a rising ratio of GSSG/GSH, but not with a drop of GSH. These results suggest that the MPP+-triggered oxidative stress may play a more important role than the loss of the antioxidant GSH in determining neuronal injury. Interestingly, the neuronal damage and oxidative stress elicited by co-treatment of BSO with MPP+ were effectively reduced by melatonin. Our results hence provide direct evidence showing that melatonin attenuates MPP+-induced nigrostriatal dopaminergic injury by its ability to impede the increase of GSSG/GSH ratio; therefore melatonin may have therapeutic implications in PD.
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PMID:Melatonin attenuates MPP+-induced neurodegeneration and glutathione impairment in the nigrostriatal dopaminergic pathway. 1198 97

Free radicals are involved in the pathogenesis and/or progression of Parkinson's disease (PD). Several ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and to show a neuroprotective effect in vivo. We investigated the in vitro free radical scavenging and antioxidant activities of cabergoline, a long-acting ergot DA agonist, as well as its ability to activate glutathione (GSH), catalase (Cat) and superoxide dismutase (SOD) activating effects and its in vivo neuroprotective properties against 6-hydroxydopamine (6-OHDA) intracerebroventricularly (i.c.v.) in mice. The striatal DA turnover induced by i.c.v. injection of 6-OHDA was completely normalized by pretreatment with cabergoline. Moreover, cabergoline scavenged free radicals in vitro and significantly reduced lipid peroxidation in vitro and in vivo. Furthermore, daily administration of cabergoline to mice significantly increased striatal GSH levels by activation of RNA expressions of GSH-related enzymes, although striatal Cat and SOD activities did not change. In addition, our present results suggest that repeated administration of cabergoline attenuates both 6-OHDA-induced nigrostriatal DAergic dysfunction and DA neuronal cell death, since cabergoline also had a neuroprotective effect in the immunohistochemical experiment. In conclusion, our findings indicate that the multiple antioxidant mechanisms of cabergoline, such as activation of the GSH system and the direct free radical scavenging activity, may explain the neuroprotective effect of this ergot DA agonist.
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PMID:The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals. 1210 44

To investigate the effects of dopamine (DA) on the release of glutathione (GSH) from astrocytes, we used astroglia-rich primary cultures from the brains of newborn rats. In the absence of DA, GSH accumulated in the medium of these cultures with a constant rate. In contrast, during incubation of the cells with 50 micro m DA extracellular GSH was not detectable anymore. This disappearance of extracellular GSH was prevented by superoxide dismutase, indicating that DA does not affect GSH release but rather reacts with the released GSH in a superoxide-dependent reaction. Incubation of astroglial cultures with 0.5 and 1 mm DA established almost constant extracellular concentrations of H2O2 of 5 microm and 15 microm, respectively. Under these conditions astroglial cultures release glutathione disulphide (GSSG). This GSSG export was blocked by catalase and by MK571, an inhibitor of the multidrug resistance protein 1. The effects of DA on the extracellular accumulations of GSH and GSSG were not modulated by inhibitors of DA receptors, DA transport, and monoamine oxidases. The other catecholamines adrenaline and noradrenaline showed similar effects on the accumulation of GSH and GSSG in the medium compared with those obtained for DA. In conclusion, the data presented demonstrate that DA affects astroglial GSH metabolism by two mechanisms: (i) directly by chemical reaction with extracellular GSH, and (ii) indirectly by generation of hydrogen peroxide that leads to the efflux of GSSG from astroglial cells. These observations are discussed in the context of the brain's GSH metabolism in Parkinson's disease.
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PMID:Effects of dopamine on the glutathione metabolism of cultured astroglial cells: implications for Parkinson's disease. 1215 71

Parkinson's disease (PD) is a progressive neurodegenerative disease involving neurodegeneration of dopaminergic neurons of the substantia nigra (SN), a part of the midbrain. Oxidative stress has been implicated to play a major role in the neuronal cell death associated with PD. Importantly, there is a drastic depletion in cytoplasmic levels of the thiol tripeptide glutathione within the SN of PD patients. Glutathione (GSH) exhibits several functions in the brain chiefly acting as an antioxidant and a redox regulator. GSH depletion has been shown to affect mitochondrial function probably via selective inhibition of mitochondrial complex I activity. An important biochemical feature of neurodegeneration during PD is the presence of abnormal protein aggregates present as intracytoplasmic inclusions called Lewy bodies. Oxidative damage via GSH depletion might also accelerate the build-up of defective proteins leading to cell death of SN dopaminergic neurons by impairing the ubiquitin-proteasome pathway of protein degradation. Replenishment of normal glutathione levels within the brain may hold an important key to therapeutics for PD. Several reports have suggested that iron accumulation in the SN patients might also contribute to oxidative stress during PD.
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PMID:Glutathione, iron and Parkinson's disease. 1221 3

Oxidative stress is believed to contribute to the pathogenesis of Parkinson's disease. One of the indices of oxidative stress is the depletion of the antioxidant glutathione (GSH), which may occur early in the development of Parkinson's disease. To study the role of GSH depletion in the survival of dopamine neurons we treated mesencephalic cultures with the GSH synthesis inhibitor L-buthionine sulfoximine. Our studies have shown that the depletion of GSH causes a cascade of events, which ultimately may result in cell death. An early event following GSH depletion is a phospholipase A(2)-dependent release of arachidonic acid. Arachidonic acid can cause damage to the GSH-depleted cells through its metabolism by lipoxygenase. The generation of superoxide radicals during the metabolism of arachidonic acid is likely to play an important role in the toxic events that follow GSH depletion.
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PMID:Glutathione depletion and oxidative stress. 1221 24

Oxidative stress is believed to play a key role in the degeneration of dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD) patients. An important biochemical feature of PD is a significant early depletion in levels of the thiol antioxidant compound glutathione (GSH) which may lead to the generation of reactive oxygen species (ROS), mitochondrial dysfunction, and ultimately to subsequent neuronal cell death. In earlier work from our laboratory, we demonstrated that depletion of GSH in dopaminergic PC12 cells affects mitochondrial integrity and specifically impairs the activity of mitochondrial complex I. Here we report that pre-treatment of PC12 cells with R-lipoic acid acts to prevent depletion of GSH content and preserves the mitochondrial complex I activity which normally is impaired as a consequence of GSH loss.
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PMID:Pre-treatment with R-lipoic acid alleviates the effects of GSH depletion in PC12 cells: implications for Parkinson's disease therapy. 1242 20


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