UMLS:C0030567 - FACTA Search

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MPP(+), an active metabolite of MPTP, causes a dopaminergic neuronal degeneration similar to that observed in Parkinson's disease. Current data suggest that MPP(+)-induced cytotoxicity may be mediated by oxygen free radicals. To evaluate this hypothesis, we first investigated whether MPP(+) could cause oxidative stress by producing oxygen free radicals in the SH-SY5Y, human neuroblastoma cell line. MPP(+) was toxic to the cells dose-dependently but did not increase the level of lipid peroxidation at toxic concentrations. Second, we examined the effects of various antioxidants and an inhibitor of nitric oxide synthase (NOS) on the development of MPP(+) cytotoxicity. Pretreatment with antioxidants such as ascorbic acid, Trolox, phenyl-tertiary-butyl-nitrone (PBN), which show protective effects on tert-butyl hydroperoxide (tBOOH) toxicity did not attenuate MPP(+) cytotoxicity. Similarly, the combination of antioxidant enzymes, SOD and catalase (50 U/ml, respectively), did not protect the cells from the toxic action of MPP(+). Also N-nitro-l-arginine methyl ester (NAME), a competitive inhibitor of NOS, and combined incubation with NAME and antioxidant enzymes failed to attenuate MPP(+) cytotoxicity. On the other hand, a sublethal dose of MPP(+) potentiated iron and H(2)O(2)-induced cytotoxicity. These results suggest that oxygen free radicals may not be a primary cause of MPP(+)-induced cell death but that MPP(+) increases the vulnerability of cells to oxidative stress.
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PMID:MPP(+) increases the vulnerability to oxidative stress rather than directly mediating oxidative damage in human neuroblastoma cells. 1096 95

A potent inhibitor of type B monoamine oxidase, (-)deprenyl, is known to protect or rescue dying neurons, independent of inhibition of the enzyme activity. After long term administration to rodents, a propargylamine structurally related to (-)deprenyl, (R)(+)-N-propargyl-1-aminoindan (rasagiline) increased the activities of anti-oxidative enzymes, superoxide dismutase and catalase. Rasagiline protected in vitro dopamine cells from apoptosis induced by oxidative stress or neurotoxins. The mechanism of the anti-apoptotic effect was studied by in vitro experiments using human dopaminergic neuroblastoma, SH-SY5Y cells. Peroxynitrite-generating N-morpholino sydonimine (SIN-1) induced apoptosis in SH-SY5Y cells via disruption of mitochondrial membrane potential (DeltaPsim), followed by caspase 3 activation. Rasagiline prevented the loss of DeltaPsim, the initial step to apoptosis, and also following caspase 3-activation and DNA fragmentation. The results suggest that rasagiline may interact with the specific molecule in the mitochondria and suppress the death signal transduction. By the anti-apoptotic function, rasagiline may rescue or protect declining neurons in aging and neurodegenerative disorders, such as Parkinson's disease.
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PMID:Mechanism underlying anti-apoptotic activity of a (-)deprenyl-related propargylamine, rasagiline. 1099 18

Oxidative stress has been implicated in the selective degeneration of dopaminergic (DAergic) neurons in Parkinson's disease (PD). In this study, we tested the efficacy of EUK-134, a superoxide dismutase (SOD) and catalase mimetic, on the nitration of tyrosine hydroxylase (TH), a marker of oxidative stress, and neurotoxicity produced by 1-methyl-4-phenylpyridinium (MPP(+)) and 6-hydroxydopamine (6-OHDA) in primary DAergic neuron cultures. Exposure of cultures to 10 microM MPP(+) reduced dopamine (DA) uptake and the number of tyrosine hydroxylase immunoreactive (THir) neurons to 56 and 52% of control, while exposure to 30 microM 6-OHDA reduced DA uptake and the number of THir neurons to 58 and 59% of control, respectively. Pretreatment of cultures with 0.5 microM EUK-134 completely protected DAergic neurons against MPP(+)- and 6-OHDA-induced neurotoxicity. Exposure of primary neuron cultures to either MPP(+) or 6-OHDA produced nitration of tyrosine residues in TH. Pretreatment of cultures with 0.5 microM EUK-134 completely prevented MPP(+)- or 6-OHDA-induced nitration of tyrosine residues in TH. Taken together, these results support the idea that reactive oxygen species (ROS) are critically involved in MPP(+)- and 6-OHDA-induced neurotoxicity and suggest a potential therapeutic role for synthetic catalytic scavengers of ROS, such as EUK-134, in the treatment of PD.
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PMID:Prevention of 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced nitration of tyrosine hydroxylase and neurotoxicity by EUK-134, a superoxide dismutase and catalase mimetic, in cultured dopaminergic neurons. 1103 57

Two substances which are products of the isoprenoid pathway, can participate in lipid peroxidation. One is digoxin, which by inhibiting membrane Na(+)-K+ ATPase, causes increase in intracellular Ca2+ and depletion of intracellular Mg2+, both effects contributing to increase in lipid peroxidation. Ubiquinone, another products of the pathway is a powerful membrane antioxidant and its deficiency can also result in defective electron transport and generation of reactive oxygen species. In view of this and also in the light of some preliminary reports on alteration in lipid peroxidation in neuropsychiatric disorders, a study was undertaken on the following aspects in some of these disorders (primary generalised epilepsy, schizophrenia, multiple sclerosis, Parkinson's disease and CNS glioma)--1) concentration of digoxin, ubiquinone, activity of HMG CoA reductase and RBC membrane Na(+)-K+ ATPase 2) activity of enzymes involved in free radical scavenging 3) parameters of lipid peroxidation and 4) antioxidant status. The result obtained indicates an increase in the concentration of digoxin and activity of HMG CoA reductase, decrease in ubiquinone levels and in the activity of membrane Na(+)-K+ ATPase. There is increased lipid peroxidation as evidenced from the increase in the concentration of MDA, conjugated dienes, hydroperoxides and NO with decreased antioxidant protection as indicated by decrease in ubiquinone, vit E and reduced glutathione in schizophrenia, Parkinson's disease and CNS glioma. The activity of enzymes involved in free radical scavenging like SOD, catalase, glutathione peroxidase and glutathione reductase is decreased in the above diseases. However, there is no evidence of any increase in lipid peroxidation in epilepsy or MS. The role of increased operation of the isoprenoid pathway as evidenced by alteration in the concentration of digoxin and ubiquinone in the generation of free radicals and protection against them in these disorders is discussed.
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PMID:Isoprenoid pathway and free radical generation and damage in neuropsychiatric disorders. 1127 6

A series of neurotoxic tetrahydroisoquinoline alkaloids has been detected in certain regions of mammalian brains. One such dopaminergic tetrahydroisoquinoline neurotoxin is salsolinol (SAL), which is suspected of being associated with the etiology of Parkinson's disease and neuropathology of chronic alcoholism. In the present study, we found that SAL in combination with Cu(II) induced strand scission in pBR322 and phiX174 supercoiled DNA, which was inhibited by the copper chelator, reactive oxygen species (ROS) scavengers, reduced glutathione, and catalase. SAL in the presence of Cu(II) caused hydroxylation of salicylic acid to produce 2,3- and 2,5-dihydroxybenzoic acids. Reaction of calf thymus DNA with SAL plus Cu(II) resulted in substantial oxidative DNA damage as determined by 8-hydroxydeoxyguanosine (8-OH-dG) formation. Blockade of the dihydroxy functional group of SAL abolished its capability to yield 8-OH-dG in the presence of Cu(II). The dehydro analog of SAL, 1-methyl-6,7-dihydroxy-3,4-dihydroisoquinoline, produced significantly high levels of 8-OH-dG when incubated with calf thymus DNA, even in the absence of Cu(II), which appears to be attributable to the tautomer formation by this compound. In another experiment, SAL exerted cytotoxicity when treated to rat pheochromocytoma (PC12) cells. Based on these findings, it seems likely that SAL undergoes redox cycling in the presence of Cu(II) with concomitant production of ROS, particularly hydroxyl radical, which could contribute to DNA damaging and cytotoxic properties of this neurotoxin.
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PMID:Oxidative DNA damage and cytotoxicity induced by copper-stimulated redox cycling of salsolinol, a neurotoxic tetrahydroisoquinoline alkaloid. 1139 Jan 86

The cellular pathways underlying naturally occurring neuronal apoptosis in the rat substantia nigra (SN) during the perinatal period remain largely unknown. Determining the mediators of this process in development may shed light on causes of premature neuronal death in adult neurodegenerative disorders, including the loss of dopamine neurons in Parkinson's disease. In the present study, we investigated whether lipid peroxidation-mediated oxidative stress mediates developmental death of nigral neurons by (1) establishing the profile of lipid peroxidation and other oxidative stress markers throughout the postnatal period both in the SN and striatum, and (2) examining whether the inhibitor of lipid peroxidation, alpha-tocopherol, protects these neurons from death. In addition to monitoring, the level of lipid peroxidation throughout development, we also measured the activities of three antioxidant enzymes, namely superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). We have shown that lipid peroxidation and SOD activity progressively increased from postnatal day (PND) 3 to PND 42 in both SN and striatum. During this period, GPx activity remained stable, while catalase activity transiently increased at PND 8 only in the SN. Furthermore, alpha-tocopherol treatment from embryonic day 18 to PND 2 did not reduce the number of apoptotic neurons at PND 3. These results do not support the hypothesis that lipid peroxidation-mediated oxidative stress is the major mediator of nigral dopamine neuronal apoptosis during the perinatal period.
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PMID:Lipid peroxidation-mediated oxidative stress and dopamine neuronal apoptosis in the substantia nigra during development. 1140 91

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

In the present study we demonstrate neuroprotective property of green tea extract and (-)-epigallocatechin-3-gallate in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice model of Parkinson's disease. N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxin caused dopamine neuron loss in substantia nigra concomitant with a depletion in striatal dopamine and tyrosine hydroxylase protein levels. Pretreatment of mice with either green tea extract (0.5 and 1 mg/kg) or (-)-epigallocatechin-3-gallate (2 and 10 mg/kg) prevented these effects. In addition, the neurotoxin caused an elevation in striatal antioxidant enzymes superoxide dismutase (240%) and catalase (165%) activities, both effects being prevented by (-)-epigallocatechin-3-gallate. (-)-Epigallocatechin-3-gallate itself also increased the activities of both enzymes in the brain. The neuroprotective effects are not likely to be caused by inhibition of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine conversion to its active metabolite 1-methyl-4-phenylpyridinium by monoamine oxidase-B, as both green tea and (-)-epigallocatechin-3-gallate are very poor inhibitors of this enzyme in vitro (770 microg/mL and 660 microM, respectively). Brain penetrating property of polyphenols, as well as their antioxidant and iron-chelating properties may make such compounds an important class of drugs to be developed for treatment of neurodegenerative diseases where oxidative stress has been implicated.
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PMID:Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. 1155 81

Antioxidant profiles in Parkinson's disease (PD; n = 15), dementias of Alzheimer's type (DAT; 18) and Vascular (VD; 15), and control subjects (C; 14) were studied. Cu-Zn superoxide dismutase (SOD), catalase (CAT), glutathione system (GLU) and thiobarbituric acid reactive substances (TBARS) were measured in erythrocytes; antioxidant capacity (TRAP) in plasma. Biochemical variables were analyzed simultaneously using multi-variate and non-parametric methods. Clinical diagnostic resulted associated with the main source of variability in antioxidant variables (Kruskal-Wallis: H = 32.58, p = 0.000001). Comparison of PD and C resulted highly significant (z = 4.47, p = 0.000047), demonstrating an association between oxidative stress and PD. SOD and TBARS were significantly higher in pathological groups against C (p = 0.0000001, p = 0.051); TRAP resulted lower (p = 0.00015). Discriminant functions constructed using biochemical variables separated pathological groups (93% success) from C, and DAT (88.9%) from VD (73.3%); but not PD from DAT or VD. Antioxidant profiles of PD patients showed characteristics overlapping with DAT (60%) and with VD (40%), suggesting biochemical similarities between them.
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PMID:Parkinson's disease is associated with oxidative stress: comparison of peripheral antioxidant profiles in living Parkinson's, Alzheimer's and vascular dementia patients. 1172 16

Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B.
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PMID:Neuroprotective actions of selegiline. 1181 32

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