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)

Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. We have generated dopaminergic PC12 cell lines in which levels of GSH can be inducibly down-regulated via doxycycline induction of antisense messages against both the heavy and light subunits of gamma-glutamyl-cysteine synthetase, the rate-limiting enzyme in glutathione synthesis. Down-regulation of glutamyl-cysteine synthetase results in reduction in mitochondrial GSH levels, increased oxidative stress, and decreased mitochondrial function. Interestingly, decreases in mitochondrial activities in GSH-depleted PC12 cells appears to be because of a selective inhibition of complex I activity as a result of thiol oxidation. These results suggest that the early observed GSH losses in the SN may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with PD.
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PMID:Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease. 1084 69

Depletion of glutathione in the substantia nigra is one of the earliest changes observed in Parkinson's disease (PD), and could initiate dopaminergic neuronal degeneration. Nevertheless, we have previously demonstrated that mesencephalic dopaminergic neurons in primary monolayer cultures are more resistant to the toxicity of glutathione depletion than nondopaminergic neurons. To extend this finding to a system that more closely resembles the in vivo situation, we characterized the effects of glutathione depletion on reaggregate cultures derived from ventral mesencephalic and their striatal target neurons, as well as supporting elements including glia. Dopaminergic neurons were found to be more resistant to the toxicity of buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis, than other nigrostriatal neurons, while striatal target cells exhibited an intermediate susceptibility when examined after 48 h. Glutathione depletion, however, decreased the intracellular content of catecholamines after 48 h and eventually led to the loss of dopaminergic neurons after 7 days. Our data indicate that the intrinsic resistance of dopaminergic neurons to the toxicity of glutathione depletion occurs in a variety of experimental paradigms, and suggest that global glutathione depletion alone is unlikely to account for the selective loss of dopaminergic neurons in PD. Rather, it is more likely that either the selective loss of glutathione from dopaminergic neurons, or the combination of glutathione loss with other insults contributes to the preferential death of dopaminergic neurons in PD.
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PMID:Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system. 1093 May 45

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.
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PMID:Glutathione, oxidative stress and neurodegeneration. 1093 Nov 72

Dopamine may contribute to the loss of dopamine neurons in Parkinson's disease by generating reactive oxygen species and quinones. A previous report from this laboratory showed that intrastriatal injection of dopamine resulted in the selective reduction of tyrosine hydroxylase immunoreactivity, accompanied by an increase in indices of dopamine oxidation. However, conclusive proof that decreased tyrosine hydroxylase immunoreactivity represented a loss of dopamine terminals was lacking. In this paper, we demonstrate that injection of dopamine results in a selective loss of dopamine terminals by (i) showing that immunoreactivity for another selective marker for dopamine terminals, the dopamine transporter, is also reduced; and (ii) that amino-cupric-silver stain reveals terminal degeneration within the area of selective loss of dopamine terminals. To determine the dopamine concentration that is selectively toxic to dopamine terminals, we examined changes in extracellular dopamine and 3,4-dihydroxyphenylacetic acid in the area of selective terminal loss following intrastriatal dopamine. Dopamine and 3,4-dihydroxyphenylacetic acid in this region reached peak levels 1-2h after the injection, and then returned towards baseline. The peak level of dopamine in the area of selective dopamine terminal damage was 10(2)-10(3)-fold lower than the injected concentration. Changes in striatal tissue levels of cysteinyl-catechols and glutathione were examined at 2, 4, 8, and 24h after intrastriatal dopamine. Levels of protein cysteinyl-dopamine and cysteinyl-3,4-dihydroxyphenylacetic acid were increased at all time-points following the dopamine injection. High levels of free cysteinyl-catechols and glutathione-dopamine were detected within 2h after the dopamine injection. Glutathione levels were decreased significantly at 4 and 8h after the injection of dopamine, and returned to control levels by 24h. These data indicate that dopamine terminals actively degenerate following a single intrastriatal injection of dopamine, and furthermore that oxidative stress plays a key role in this process. As oxidative stress is thought to play an active role in the pathobiology of Parkinson's disease, these data may be relevant to our understanding of the disorder.
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PMID:Role of oxidative changes in the degeneration of dopamine terminals after injection of neurotoxic levels of dopamine. 1106 37

Redox changes within neurones are increasingly being implicated as an important causative agent in brain ageing and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). Cells have developed a number of defensive mechanisms to maintain intracellular redox homeostasis, including the glutathione (GSH) system and antioxidant enzymes. Here we examine the effects of N-acetyl-L-cysteine (NAC) on beta-amyloid (A beta) secretion and tau phosphorylation in SHSY5Y neuroblastoma cells after exposure to oxidative stress inducing/cytotoxic compounds (H(2)O(2), UV light and toxic A beta peptides). A beta and tau protein are hallmark molecules in the pathology of AD while the stress factors are implicated in the aetiology of AD. The results show that H(2)O(2), UV light, A beta 1-42 and toxic A beta 25-35, but not the inactive A beta 35-25, produce a significant induction of oxidative stress and cell cytotoxicity. The effects are reversed when cells are pre-treated with 30 mM NAC. Cells exposed to H(2)O(2), UV light and A beta 25-35, but not A beta 35-25, secrete significantly higher amounts of A beta 1-40 and A beta 1-42 into the culture medium. NAC pre-treatment increased the release of A beta 1-40 compared with controls and potentiated the release of both A beta 1-40 and A beta 1-42 in A beta 25-35-treated cells. Tau phosphorylation was markedly reduced by H(2)O(2) and UV light but increased by A beta 25-35. NAC strongly lowered phospho-tau levels in the presence or absence of stress treatment.
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PMID:N-acetyl-L-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: effects on beta-amyloid secretion and tau phosphorylation. 1114 96

Mutations in alpha-synuclein (A30P and A53T) are involved in some cases of familial Parkinson's disease (FPD), but it is not known how they result in nigral cell death. We examined the effect of alpha-synuclein overexpression on the response of cells to various insults. Wild-type alpha-synuclein and alpha-synuclein mutations associated with FPD were overexpressed in NT-2/D1 and SK-N-MC cells. Overexpression of wild-type alpha-synuclein delayed cell death induced by serum withdrawal or H(2)O(2), but did not delay cell death induced by 1-methyl-4-phenylpyridinium ion (MPP(+)). By contrast, wild-type alpha-synuclein transfectants were sensitive to viability loss induced by staurosporine, lactacystin or 4-hydroxy-2-trans-nonenal (HNE). Decreases in glutathione (GSH) levels were attenuated by wild-type alpha-synuclein after serum deprivation, but were aggravated following lactacystin or staurosporine treatment. Mutant alpha-synucleins increased levels of 8-hydroxyguanine, protein carbonyls, lipid peroxidation and 3-nitrotyrosine, and markedly accelerated cell death in response to all the insults examined. The decrease in GSH levels was enhanced in mutant alpha-synuclein transfectants. The loss of viability induced by toxic insults was by apoptosic mechanism. The presence of abnormal alpha-synucleins in substantia nigra in PD may increase neuronal vulnerability to a range of toxic agents.
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PMID:Effect of the overexpression of wild-type or mutant alpha-synuclein on cell susceptibility to insult. 1118 19

Recent studies provide evidence that phospholipase A2 (PLA2) may play a role in the development of experimental parkinsonism. In this investigation an attempt was made to determine a possible protective effect of quinacrine (QNC), a PLA2 inhibitor on MPTP as well as 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in rodents. For MPTP studies, adult male mice (C57 BL) were treated with MPTP (30 mg/kg, i.p.) daily for 5 days. QNC was injected i.p. in the doses of 0, 10, 30 and 60 mg/kg daily 30 min before MPTP in four different groups. Two other groups of mice received either vehicle (control) or a high dose of QNC (60 mg/kg). Two hours after the last injection of MPTP, striata were collected for the analysis of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and glutathione (GSH). For the 6-OHDA study, male Wistar rats were infused with 6-OHDA (60 microg) in the right striatum under chloral hydrate anesthesia. The rats in different groups were treated with 0, 5, 15 and 30 mg/kg QNC (i.p.) for 4 days, while first injection was given 30 min before 6-OHDA. On day 5, rats were sacrificed and striata were stored at -80 degrees C. Administration of MPTP or 6-OHDA significantly reduced striatal DA, which was significantly attenuated by QNC. Concomitant treatment with QNC also protected animals against MPTP or 6-OHDA-induced depletion of striatal GSH. Our findings clearly suggest the role of PLA2 in MPTP and 6-OHDA induced neurotoxicity and oxidative stress. However, further studies are warranted to explore the therapeutic potential of PLA2 inhibitors for the treatment of Parkinson's disease.
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PMID:Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of Parkinsonism in rodents. 1122 16

Oxidative stress and highly specific decreases in glutathione (GSH) are associated with nerve cell death in Parkinson's disease. Using an experimental nerve cell model for oxidative stress and an expression cloning strategy, a gene involved in oxidative stress-induced programmed cell death was identified which both mediates the cell death program and regulates GSH levels. Two stress-resistant clones were isolated which contain antisense gene fragments of the translation initiation factor (eIF)2alpha and express a low amount of eIF2alpha. Sensitivity is restored when the clones are transfected with full-length eIF2alpha; transfection of wild-type cells with the truncated eIF2alpha gene confers resistance. The phosphorylation of eIF2alpha also results in resistance to oxidative stress. In wild-type cells, oxidative stress results in rapid GSH depletion, a large increase in peroxide levels, and an influx of Ca(2+). In contrast, the resistant clones maintain high GSH levels and show no elevation in peroxides or Ca(2+) when stressed, and the GSH synthetic enzyme gamma-glutamyl cysteine synthetase (gammaGCS) is elevated. The change in gammaGCS is regulated by a translational mechanism. Therefore, eIF2alpha is a critical regulatory factor in the response of nerve cells to oxidative stress and in the control of the major intracellular antioxidant, GSH, and may play a central role in the many neurodegenerative diseases associated with oxidative stress.
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PMID:Regulation of antioxidant metabolism by translation initiation factor 2alpha. 1123 55

In order to establish whether the antioxidant and iron-chelating activities of R-apomorphine (R-APO), a D(1)-D(2) receptor agonist, may contribute to its neuroprotective property, its S-isomer, which is not a dopamine agonist, was studied. The neuroprotective property of R- and S-APO has been studied in the MPTP model of Parkinson's disease (PD). Both S-APO (0.5-1 mg/kg, subcutaneous) and R-APO (10 mg/kg) pretreatment of C57-BL mice, protected against MPTP (24 mg/kg, intraperitoneally) induced dopamine (DA) depletion and reduction in tyrosine hydroxylase (TH) activity. However, only R-APO prevented nigro-striatal neuronal cell degeneration, as indicated by the immunohistochemistry of TH positive neurones in substantia nigra and by western analysis of striatal TH content. R-APO prevented the reduction of striatal-GSH and the increase in the ratio of GSSG over total glutathione, caused by MPTP treatment. In vitro both R-APO and S-APO inhibited monoamine oxidase A and B activity at relatively high concentrations (100 and 300 micromol/L, respectively). The elevated activity of TH induced by the two enantiomers may contribute to the maintenance of normal DA levels, suggesting that one of the targets of these molecules may involve upregulation of TH activity. It is suggested that the antioxidant and iron-chelating properties, possible monoamine oxidase inhibitory actions, together with activation of DA receptors, may participate in the mechanism of neuroprotection by APO enantiomers against MPTP.
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PMID:Effects of R- and S-apomorphine on MPTP-induced nigro-striatal dopamine neuronal loss. 1127 70

A growing body of evidence has implicated oxidative stress as an important factor in the neuropathology associated with Parkinson's disease. Dopaminergic nigrostriatal neurons, the predominant cells lost in Parkinson's, are believed to be highly prone to oxidative damage due to the propensity for dopamine to auto-oxidize and thereby produce elevated levels of hydrogen peroxide and catecholamine quinones. Hydrogen peroxide formed during this process can either be converted by iron to form highly reactive hydroxyl radicals or removed through reduction by glutathione. Glutathione can also conjugate with quinones formed during dopamine oxidation preventing them from facilitating the release of iron from the iron-storage molecule ferritin. Alterations in both iron and glutathione levels in the substantia nigra have been correlated with the neuronal degeneration accompanying Parkinson's disease but a direct causative role for either has yet to be definitively proved. We will discuss the use of genetically engineered cell and mouse lines generated in our laboratory as models to examine the role that alterations in iron and glutathione levels may play in neurodegeneration of dopaminergic neurons of the substantia nigra associated with Parkinson's disease, and how these two parameters may interact with one another to bring this about.
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PMID:Do alterations in glutathione and iron levels contribute to pathology associated with Parkinson's disease? 1128 21


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