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)

Brain-derived neurotrophic factor (BDNF) has recently been shown to enhance the survival of dopamine neurons in cultures derived from the embryonic rat mesencephalon. We now extend this study by demonstrating that, in addition to the effect of sustaining survival of dopaminergic neurons, BDNF also confers protection against the neurotoxic effects of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenylpyridinium ion (MPP+). Exposure of mesencephalic cultures to either 6-OHDA or MPP+ resulted in a loss of 70-80% of dopaminergic neurons, as determined by tyrosine hydroxylase (TH) immunocytochemistry. In BDNF-treated cultures, loss of TH-positive cells after exposure to either toxin was reduced to only 30%. To facilitate biochemical measurements, we studied SH-SY5Y dopaminergic neuroblastoma cells. BDNF was found to protect these cells from the dopaminergic neurotoxins, 6-OHDA and MPP+. Indicative of oxidative stress, treatment of SH-SY5Y cells with 10 microM 6-OHDA for 24 h caused a fivefold increase in the levels of oxidized glutathione (GSSG). Pretreatment with BDNF for 24 h completely prevented the rise in GSSG. Further examination revealed that BDNF increased the activity of the protective enzyme, glutathione reductase, by 100%. In contrast, BDNF had no effect on the activity of catalase. These results add further impetus to exploring the therapeutic potential of BDNF in animal models of Parkinson's disease.
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PMID:Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: involvement of the glutathione system. 845 44

Human brain levels of glutathione (GSH), glutathione disulfide (GSSG), and vitamin E were measured in neurologically normal control patients and two groups of patients with neurodegeneration: those with Alzheimer's disease (AD), and AD with some features of Parkinson's disease (AD-PD). Control brain samples contained GSH levels more than 50 times higher than GSSG. The levels of GSH were highest in the caudate nucleus and lowest in the medulla. In patients with AD or AD-PD, hippocampal levels of GSH were significantly higher than controls. Patients with AD also demonstrated high GSH levels in the midbrain compared to normal. In contrast, patients with AD-PD did not have significantly elevated GSH levels in this site. GSSG levels were not significantly different in any brain region between controls and diseased patients. In control brains, the medulla had higher levels of vitamin E than any other brain region. The caudate nucleus had the lowest levels, which were about half the levels in the medulla. Control levels of vitamin E in the midbrain were about 18.8 micrograms/g. In AD patients the midbrain levels of vitamin E doubled to 42.3 micrograms/g. This doubling also occurred in AD-PD patients where midbrain vitamin E levels increased to 44.0 micrograms/g. These results may indicate that compensatory increases in GSH and vitamin E levels occur following damage to specific brain regions in patients with AD or AD-PD.
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PMID:Alzheimer's and Parkinson's disease. Brain levels of glutathione, glutathione disulfide, and vitamin E. 195 64

Glutathione disulfide, the major cellular disulfide, releases zinc from metallothionein (MT) [W. Maret (1994) Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange, Proc. natn. Acad. Sci. U.S.A. 91, 237-241]. Here, the interaction of rabbit liver MT-II with other selected biological disulfides (coenzyme A/glutathione mixed disulfide, coenzyme A disulfide, and cystamine) was investigated by measuring concomitant release of radioactive 65-zinc from MT. These disulfides react more rapidly than glutathione disulfide, thus underscoring the reactivity of zinc sulfur bonds in the clusters of MT and the importance of the MT/disulfide interaction as a chemical mechanism for mobilizing zinc from a thermodynamically stable zinc complex. Two implications of these in vitro findings are discussed. (i) Apparently, in the case of zinc which is redox inert, Nature has availed itself of the redox activity of the cysteine ligand to mobilize the metal, and, presumably to permit redox-control of cellular zinc distribution. The mobilization of zinc from MT suggests a possible function of MT as a physiological zinc donor. (ii) A shift of the glutathione redox balance under conditions of oxidative stress will accelerate metal release from MT. Such a disturbance of metal metabolism has important consequences for the progression of diseases such as Alzheimer's and Parkinson's disease where oxidative stress occurs in affected brain tissue.
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PMID:Metallothionein/disulfide interactions, oxidative stress, and the mobilization of cellular zinc. 765 43

In the cerebrospinal fluid of untreated patients with Parkinson's disease (PD) the concentrations of reduced glutathione (GSH) and alpha-tocopherol (alpha-TOH) were unaltered but the concentration of oxidized glutathione (glutathione disulfide, GSSG) (P < 0.001), the GSSG/GSH ratio (P < 0.06), alpha-tocopherol quinone (alpha-TQ) (P < 0.001), and the alpha-TQ/alpha-TOH ratio (P < 0.01) were reduced significantly. In L-dopa-treated patients, the concentrations of GSH, GSSG, and the alpha-TQ concentration and the alpha-TQ/alpha-TOH ratio (P < 0.05) increased compared with untreated PD patients. These results suggest that oxidation of GSH and alpha-TOH is decreased in untreated PD patients, but is activated to a control level or more after L-dopa treatment.
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PMID:Reduced and oxidized forms of glutathione and alpha-tocopherol in the cerebrospinal fluid of parkinsonian patients: comparison between before and after L-dopa treatment. 773 98

Reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were measured in various brain areas (substantia nigra, putamen, caudate nucleus, globus pallidus, and cerebral cortex) from patients dying with Parkinson's disease, progressive supranuclear palsy, multiple-system atrophy, and Huntington's disease and from control subjects with no neuropathological changes in substantia nigra. GSH levels were reduced in substantia nigra in Parkinson's disease patients (40% compared to control subjects) and GSSG levels were marginally (29%) but insignificantly elevated; there were no changes in other brain areas. The only significant change in multiple-system atrophy was an increase of GSH (196%) coupled with a reduction of GSSG (60%) in the globus pallidus. The only change in progressive supranuclear palsy was a reduced level of GSH in the caudate nucleus (51%). The only change in Huntington's disease was a reduction of GSSG in the caudate nucleus (50%). Despite profound nigral cell loss in the substantia nigra in Parkinson's disease, multiple-system atrophy, and progressive supranuclear palsy, the level of GSH in the substantia nigra was significantly reduced only in Parkinson's disease. This suggests that the change in GSH in Parkinson's disease is not solely due to nigral cell death, or entirely explained by drug therapy, for multiple-system atrophy patients were also treated with levodopa. The altered GSH/GSSG ratio in the substantia nigra in Parkinson's disease is consistent with the concept of oxidative stress as a major component in the pathogenesis of nigral cell death in Parkinson's disease.
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PMID:Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. 808 Feb 39

The activities of enzymes related to glutathione synthesis, degradation, and function were analyzed in various brain regions (cerebral cortex, caudate nucleus, putamen, globus pallidus, and substantia nigra) from patients dying with pathologically proven Parkinson's disease (PD) and multiple system atrophy (MSA), and from matched controls with no neurological disorder. The activity of the glutathione degradative enzyme, gamma-glutamyltranspeptidase, was selectively elevated in substantia nigra (SN) in PD. In contrast, the activity of the synthetic enzyme, gamma-glutamylcysteine synthetase, was unaltered in SN and other brain areas in PD. Similarly, glutathione peroxidase and glutathione transferase activities were unaltered in SN or in other brain regions in PD. gamma-Glutamylcysteine synthetase, gamma-glutamyltranspeptidase, glutathione peroxidase, and glutathione transferase activities were normal in SN and most other brain areas in MSA. However, glutathione peroxidase activity was increased in the lateral globus pallidus and caudate nucleus in MSA. The depletion of reduced glutathione (GSH) in the SN in PD, with no change in oxidized glutathione (GSSG), may be due to efflux of GSH mainly out of glia promoted by gamma-glutamyltranspeptidase, perhaps with additional increased conversion of GSH to GSSG (which itself is transported out of cells by gamma-glutamyltranspeptidase), in response to increased hydrogen peroxide formation.
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PMID:Glutathione-related enzymes in brain in Parkinson's disease. 808 Feb 39

Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO). Here we show that the two are linked. Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport. MAO inhibitors prevent this action. Mitochondrial damage is also reversed during electron flow. A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function. In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport. In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria. These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover. The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.
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PMID:Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow. 914 60

In Parkinson's disease (PD), a compensatory increase in dopamine (DA) turnover occurs in the remaining nigrostriatal dopaminergic neurons, resulting in greater exposure of each neuron to hydrogen peroxide (H2O2) derived from oxidative deamination of DA. The formation of oxyradicals from H2O2 is regarded as a mechanism that could contribute to the progression of PD, and incubation of rat striatal synaptosomes with levodopa (LD) results in an increase in oxidized glutathione (GSSG), indicative of oxidant stress. The present study was undertaken to determine whether striatal GSSG levels increase in response to administration of LD in vivo. Acute and repeated (3-week) treatment of normal rats with LD at doses of up to 100 mg/kg did not increase striatal GSSG despite marked increase in DA turnover. These results suggest that intact striatum may possess increased defense capacity against oxidant stress generated by increased DA turnover as compared with isolated synaptosomes.
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PMID:Effects of enhanced striatal dopamine turnover in vivo on glutathione oxidation. 931 85

In this study a chronic cerebral iron-loaded model was established by feeding mice with high iron diet. Data indicated that brain iron concentrations were significantly increased in iron-fed mice compared with those of controls. A significant increase in oxidized glutathione (GSSG), decrease in total glutathione (oxidized and reduced glutathione, GSSG + GSH), and therefore increase in the GSSG/(GSSG + GSH) ratios were observed in iron-loaded mice. Hydroxyl radical (.OH) levels in striatum and brainstem were also significantly increased. Excessive iron alone did not change either dopamine (DA) or lipid peroxidation (LPO) concentrations in striatum. However, a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, i.p.) into the iron-loaded mice caused a great enhancement in all these biochemical abnormalities. These findings suggest that iron does induce oxidative stress, but not severely injury neurons per sc. Excessive iron accumulation in the brain, however, is a potential risk for neuronal damage, which may promote by triggering factor(s). This supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).
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PMID:Excessive iron accumulation in the brain: a possible potential risk of neurodegeneration in Parkinson's disease. 944 65

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


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