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)

Epidemiological studies have shown a reduced incidence of cancer in Parkinson's disease. Since nearly all parkinsonian patients with clinical impairment are treated with L-beta-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA)ergic agonists, a possibility exists that these therapeutic agents can influence the risk of cancer. We studied the antiproliferative effect of these therapeutic agents (and substances structurally correlated) on Chinese hamster ovary (CHO)-K1 cell growth. Among the compounds tested, apomorphine proved to be the most potent inhibitor of CHO-K1 cell growth, with an EC(50) of 3.35 +/- 0.12 micro M. The apomorphine analogues, apocodeine and hydroxyethylnorapomorphine, were less active as inhibitors of CHO-K1 cell growth. The activity of DA, 6-hydroxydopamine (6-OHDA), phenylethylamine (PEA), L-DOPA and bromocriptine as antiproliferative was one order of magnitude lower than that of apomorphine while pergolide was ineffective. To test whether or not the oxidative potential of these compounds was important for their antiproliferative effect, several antioxidants were assayed. Among them glutathione (GSH) and dithiothreitol (DTT) were effective in reversing the anti-proliferative effect of apomorphine, DA, 6-OHDA and PEA, conversely they did not work with bromocriptine. GSH and DTT are sulphydryl-reducing agents; while their effect could explain the efficacy against apomorphine, DA and 6-OHDA, it is difficult to understand why they should have any effect on PEA as this substance does not react with sulphydryl groups. The oxidative potential as a mechanism of action was also questioned by the results obtained with dihydrorhodamine 123, a probe that changes its fluorescent emission wave when oxidized. None of the compounds, with the exception of 6-OHDA, had any effect on the fluorescent emission wave of the probe at the maximal concentrations used to inhibit CHO-K1 cell growth. At concentrations five times higher, apomorphine and DA generated reactive oxygen species but PEA and bromocriptine did not. These data demonstrate that the antiproliferative effect of these compounds is not due to their oxidative potential, but another mechanism must be postulated.
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PMID:Dopamine agonists and analogues have an antiproliferative effect on CHO-K1 cells. 1283 96

There is strong evidence that oxidative stress participates in the etiology of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In the previous studies we have already shown that a combination of alpha-tocopherol and ascorbic acid protect neurons against tert-butyl hydroperoxide (t-BuOOH) induced neurotoxicity in different brain regions including hippocampus and mid brain. In this work, we examined the neuroprotective effect of low dose of adenosine against protein oxidation (protein carbonyls) in parallel with the level of reduced glutathione (GSH) in hippocampus and mid brain regions of mouse brain. The t-BuOOH was injected intraperitoneally in three concentrations (50, 100, 150 mg/kg b.w.) for 10 days. Results showed dose dependent increase in protein carbonyl (PC) in hippocampus and mid brain region. This increase was accompanied by a significant (p < 0.05) decline in GSH content in both brain regions of t-BuOOH treated mice. Adenosine (1 mg/kg b.w.) protected both hippocampus and mid brain neurons against protein oxidation as evidenced by reduction in protein carbonyl content. The GSH content was significantly (p < 0.05) increased after the treatment of adenosine in both brain regions. These data show that prior treatment with low dose of adenosine attenuates the oxidative protein damage with parallel increase in the GSH level in hippocampus and mid brain of t-BuOOH induced mice.
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PMID:Free radical induced increase in protein carbonyl is attenuated by low dose of adenosine in hippocampus and mid brain: implication in neurodegenerative disorders. 1287 Jun 99

An evaluation is made of the effect of smoking during the period of life between 20 and 50 years of age and idiopathic Parkinson's disease in a case-control study carried out in Navarra. An inverse association is observed: for the number of smokers (OR = 0.66, CI 90% 0.41-1.05); for the number of years smoking (OR =0.22, CI 90% 0.05-0.97); and for the quantity of cigarettes smoked (z = 2.2298, p = 0.02). Likewise, a dose-response relationship exists between the number of cigarettes consumed and the risk of Parkinson's disease (p = 0.01). The same effect is maintained on analysing the data by matching 1:1 (OR = 0.59, CI 90% 0.31-1.10). All of this contributes to giving consistency to the protective effect of smoking against idiopathic Parkinson's disease. The anti-oxidant status, measured by means of different parameters in peripheral blood, is lower in the cases than in the tests for reduced glutathione (GSH) (p = 0.001) and is an independent variable with respect to smoking.
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PMID:[Inverse association between smoking and idiopathic Parkinson's disease]. 1288 57

The etiology of Parkinson's disease (PD) is still unknown. Genetic factors and environmental exposure have been suggested in the etiopathogenesis of the disease. But the cause of dopaminergic cell loss in patients with PD remains unknown. During the last decade studies of the pathogenesis of PD have centred on the oxidative damage to the substantia nigra pars compacta. An increased free radical production and an inadequate antioxidant defence system have been reported, which could contribute to the biopathology of PD. The GSH levels in the brain are decreased, and iron levels in the substantia nigra are elevated. Moreover there are changes in SOD with an increased activity in the substantia nigra. The possible implication of oxidative stress in cell loss has encouraged research into the role of certain antioxidant agents, such as dietary compounds and drugs, as protective agents against PD.
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PMID:[Oxidative stress and Parkinson's disease]. 1289 7

A decrease in total glutathione, and aberrant mitochondrial bioenergetics have been implicated in the pathogenesis of Parkinson's disease. Our previous work exemplified the importance of glutathione (GSH) in the protection of mesencephalic neurons exposed to malonate, a reversible inhibitor of mitochondrial succinate dehydrogenase/complex II. Additionally, reactive oxygen species (ROS) generation was an early, contributing event in malonate toxicity. Protection by ascorbate was found to correlate with a stimulated increase in protein-glutathione mixed disulfide (Pr-SSG) levels. The present study further examined ascorbate-glutathione interactions during mitochondrial impairment. Depletion of GSH in mesencephalic cells with buthionine sulfoximine potentiated both the malonate-induced toxicity and generation of ROS as monitored by dichlorofluorescein diacetate (DCF) fluorescence. Ascorbate completely ameliorated the increase in DCF fluorescence and toxicity in normal and GSH-depleted cultures, suggesting that protection by ascorbate was due in part to upstream removal of free radicals. Ascorbate stimulated Pr-SSG formation during mitochondrial impairment in normal and GSH-depleted cultures to a similar extent when expressed as a proportion of total GSH incorporated into mixed disulfides. Malonate increased the efflux of GSH and GSSG over time in cultures treated for 4, 6 or 8 h. The addition of ascorbate to malonate-treated cells prevented the efflux of GSH, attenuated the efflux of GSSG and regulated the intracellular GSSG/GSH ratio. Maintenance of GSSG/GSH with ascorbate plus malonate was accompanied by a stimulation of Pr-SSG formation. These findings indicate that ascorbate contributes to the maintenance of GSSG/GSH status during oxidative stress through scavenging of radical species, attenuation of GSH efflux and redistribution of GSSG to the formation of mixed disulfides. It is speculated that these events are linked by glutaredoxin, an enzyme shown to contain both dehydroascorbate reductase as well as glutathione thioltransferase activities.
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PMID:Cooperative interaction between ascorbate and glutathione during mitochondrial impairment in mesencephalic cultures. 1295 Apr 57

The consistent findings of decreased levels of the major antioxidant glutathione in substantia nigra of patients with idiopathic Parkinson's disease (PD) has provided most of the basis for the oxidative stress hypothesis of the etiology of PD. To establish whether a nigral glutathione deficiency is unique to PD, as is generally assumed, or is present in other Parkinsonian conditions associated with nigral damage, we compared levels of reduced glutathione (GSH) in postmortem brain of patients with PD to those with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). As compared with the controls, nigral GSH levels were decreased in the PD and PSP patient groups (P < 0.05 for PD [-30%], PSP [-21%]), whereas a similar decrease in the MSA patient group did not reach statistical significance (P = 0.078, MSA [-20%]). GSH levels were normal in all examined normal and degenerating extra-nigral brain areas in PSP and MSA. A trend for decreased levels of uric acid (antioxidant and product of purine catabolism) also was observed in nigra of all patient groups (-19 to -30%). These data suggest that glutathione depletion, possibly consequent to overutilisation in oxidative stress reactions, could play a causal role in nigral degeneration in all nigrostriatal dopamine deficiency disorders, and that antioxidant therapeutic approaches should not be restricted to PD.
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PMID:Nigral glutathione deficiency is not specific for idiopathic Parkinson's disease. 1450 63

Citicoline (CDP-choline or cytidine 5'-diphosphocholine) has been used as a therapeutic agent in combination with levodopa in the treatment of Parkinson's disease (PD). The present study examines the effects of citicoline by using validated in vivo and in vitro models. Citicoline reduces the cytotoxic effect of 6-hydroxydopamine (6-OHDA)-treated human dopaminergic SH-SY5Y neuroblastoma cells as measured cellular redox activity with 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) and increases the levels of reduced glutathione (GSH), a major antioxidant agent. Moreover, citicoline (500 mg/kg i.p.) administered for 7 days ameliorates functional behaviour by significantly reducing the number of apomorphine-induced contralateral rotations in 6-OHDA rats. Finally, citicoline significantly attenuates substantia nigra (SN) dopaminergic cell dropout and tyrosine hydroxylase immunoreactivity in the ipsilateral striatum in rats injected intrastriatally with 6-hydroxydopamine (6-OHDA).
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PMID:Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated SH-SY5Y human neuroblastoma cells. 1456 36

We tested the hypothesis that melatonin acts as a powerful hydroxyl radical (*OH) scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We investigated the effect of melatonin on in vitro *OH production employing a Fenton-like reaction in test tubes, and ex vivo *OH generation in isolated mitochondria induced by 1-methyl-4-phenyl pyridinium (MPP+), as well as on in vivo *OH formation in the mouse striatum following systemic administration of MPTP. We also measured reduced glutathione (GSH) levels, and superoxide dismutase (SOD) activity in the nucleus caudatus putamen (NCP) and substantia nigra (SN), 7 days following MPTP and/or melatonin administration. Melatonin caused a significant and dose-dependent inhibition of the production of *OH in the in vitro, ex vivo and in vivo experimental conditions. Melatonin caused no changes in monoamine oxidase-B activity, in vitro in mitochondrial P2 fractions or in vivo following systemic administration. MPTP treatment in mice caused a significant depletion of GSH, and increased the specific activity of SOD both in SN and NCP on the seventh day. MPTP-induced GSH depletion was dose-dependently blocked in SN and NCP by melatonin. Higher doses of melatonin exhibited a synergistic effect on MPTP-induced increase in the SOD activity in the SN. These results suggest that while GSH inhibition is a direct consequence of *OH generation following neurotoxin administration, the increase in SOD activity is a compensatory mechanism for removing superoxide radicals generated as the result of MPTP. Our results not only point to the potency of melatonin in blocking the primary insults caused by MPTP, but also provide evidence for triggering secondary neuroprotective mechanisms, suggesting its use as a therapeutic agent in neurodegenerative disorders, such as Parkinson's disease.
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PMID:Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse nigrostriatum. 1467 27

Intracellular glutathione (GSH) levels determine whether nitric oxide (NO) is neurotrophic for dopamine neurons or triggers a cell death cascade in primary midbrain cultures. We have investigated herein the role of the extracellular-signal regulated protein kinase (ERK) 1/2 pathway in this GSH switching effect. The short-lived NO donor DEA/NO induces a transient activation of ERK-1/2 that totally disappears 2 h after NO administration. The depletion of GSH increases and the supplementation of GSH suppresses ERK-1/2 activation in response to NO treatment. More interestingly, GSH depletion changes the kinetic of phosphorylation leading to a second prolonged phase of ERK-1/2 activation from 2 to 16 h after NO addition. This change of kinetic is ultimately responsible for NO toxicity under GSH-depleted conditions, because selective blockade of the second and persistent phase of activation prevents cell death. In addition, the only transient ERK activation, induced by NO under normal GSH conditions, did not cause ERK-dependent cell death. Immunocytochemical colocalization studies demonstrate that ERK activation takes place exclusively in glial cells, mainly in astrocytes and less frequently in oligodendrocytes and glial progenitors. Furthermore, glial cell elimination or inactivation in the culture, by gliotoxic drugs, abrogates NO-induced ERK activation. Our results indicate that neurotrophism of NO switches into neurotoxicity after GSH depletion due to persistent activation of the ERK-1/2 signaling pathway in glial cells. The implication of these results in pathological conditions like Parkinson's disease, where GSH depletion and NO overproduction have been documented, are discussed.
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PMID:Selective and persistent activation of extracellular signal-regulated protein kinase by nitric oxide in glial cells induces neuronal degeneration in glutathione-depleted midbrain cultures. 1469 65

The contribution of arachidonic acid (AA) release and metabolism to the toxicity that results from glutathione (GSH) depletion was studied in rat mesencephalic cultures treated with the GSH synthesis inhibitor l-buthionine sulfoximine. Our data show that GSH depletion is accompanied by increased release of AA, which is phosholipase A2 (PLA2) dependent. Exogenous AA is toxic to GSH-depleted cells. This toxicity is prevented by inhibition of lipoxygenase activity, suggesting participation of toxic byproducts of AA metabolism. Hydroxyperoxyeicosatetraenoic acid (HPETE), one of the primary products of AA metabolism by lipoxygenase is also toxic to GSH-depleted cells, whereas hydroeicosatetraenoic acid (HETE) is not. Cell death caused by GSH depletion is prevented by: (i) replenishment of GSH levels with GSH-ethyl ester; (ii) inhibition of PLA2 activity; (iii) inhibition of lipoxygenase activity; and (iv), treatment with ascorbic acid. These data suggest that the following events likely contribute to cell death when GSH levels become depleted. Loss of GSH results in increased release of AA, which is PLA2 dependent. Metabolism of arachidonic acid via the lipoxygenase pathway results in generation of oxygen free radicals possibly produced during conversion of HPETE to HETE, which contribute to cellular damage and death. Our study suggests that limiting AA release and metabolism may provide benefit in conditions with an existing depletion of GSH, such as Parkinson's disease.
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PMID:Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites. 1472 22


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