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)

The substantia nigra and globus pallidus (two iron-rich brain areas) receive a substantial innervation from the neostriatum, a considerable amount of which is GABAergic. Because of this anatomic relationship and the finding that prevention of GABA degradation in these two areas decreases their histochemical levels of iron, GABAergic transmission/metabolism may be important in regulating brain iron levels. Therefore, the present study investigated the effects of denervation of striatal/pallidal inputs to globus pallidus/substantia nigra on iron levels and associated pathologic changes in globus pallidus/substantia nigra. Adult male Sprague-Dawley rats received unilateral ibotenic acid infusions resulting in comprehensive lesions of the entire neostriatum/globus pallidus complex, or of either the anterior neostriatum or the posterior neostriatum/globus pallidus. Animals were killed at one week or one month following surgery. Between one week and one month postlesioning, comprehensive neostriatum/globus pallidus lesions induced a progressive decrease in substantia nigra volume, as well as a progressive increase in both substantia nigra zona reticularis iron staining and substantia nigra iron concentration. By one month following neostriatum/globus pallidus lesions, a marked 73% loss of substantia nigra zona reticularis neurons occurred in association with a 65% increase in glial cell numbers within zona reticularis. Compared to comprehensive neostriatum/globus pallidus lesions at the one month postlesion time point, more restricted anterior neostriatum and posterior neostriatum/globus pallidus lesions induced a less severe atrophy of the substantia nigra, a small (anterior neostriatum lesions) to moderate (posterior neostriatum/globus pallidus lesions) increase in substantia nigra zona reticularis iron staining, and either no zona reticularis neuronal loss (anterior neostriatum lesions) or limited zona reticularis neuronal loss selectively within areas of increased iron staining. These results suggest that destruction of striatal/pallidal innervation to the substantia nigra's zona reticularis induces a disruption of zona reticularis iron homeostasis, resulting in a redistribution and/or accumulation of iron in the zona reticularis and consequent zona reticularis of the substantia nigra neurodegeneration. The results further suggest that loss or dysfunction of striatonigral/striatopallidal GABAergic neurons in several neurodegenerative diseases (including Hallervorden-Spatz syndrome, progressive supranuclear palsy, multiple system atrophy, and Parkinson's disease) may result in an increase or redistribution of nigral iron to cause loss of substantia nigra neurons.
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PMID:Time-dependent changes in iron levels and associated neuronal loss within the substantia nigra following lesions within the neostriatum/globus pallidus complex. 754 96

Variation in the sialylation pattern of transferrin was studied in serum and cerebrospinal fluid (CSF) of 90 patients with Parkinson's disease (PD), dementing and non-dementing, de novo and treated, and was compared with the variation observed in a group of 21 age-matched healthy controls. In serum and CSF of PD patients the proportional contribution of the different sialo-transferrins was independent of sex or dementia. However, a significant shift was found towards the more sialylated fractions for serum transferrin in both de novo and treated PD patients. This shift was not observed for CSF transferrin. The contribution of the tau-transferrin fraction, reduced in de novo PD patients, returns on treatment to the level observed for healthy controls. These observations may be important, as the degree of sialylation of transferrin in serum and CSF plays a role in the homeostasis of iron, and suggest that alterations in transferrin sialylation may play a role in the pathophysiology of PD.
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PMID:Changed transferrin sialylation in Parkinson's disease. 755 70

The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease.
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PMID:Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. 756 81

Recent reports have stressed an accumulation of iron and enhanced levels of lipid peroxides in the substantia nigra as essential factors in the pathogenesis of Parkinson's disease. Many investigators believe that tissue antioxidants, such as ascorbate, play a protective role. On the other hand, L-DOPA, which is used extensively to treat Parkinson's disease, undergoes autoxidation (as does dopamine), thus generating reactive oxygen species. We studied lipid peroxidation (LPO) in mouse brain homogenates and evaluated the effects of iron (5 microM ferric-ADP), L-DOPA, dopamine and ascorbic acid, added either alone or in mixtures. Ascorbic acid was used at levels of 0.5 mM or 2.0 mM, approximating those present normally in brain. LPO in brain homogenates was stimulated by the addition of either ascorbic acid or iron, as well as by a combination of the two, in agreement with other reports. The effects of L-DOPA were complex: L-DOPA strongly suppressed LPO both with and without added iron-ADP. In sharp contrast, however, when ascorbic acid was also added, L-DOPA no longer suppressed LPO; indeed, L-DOPA stimulated LPO in the presence of added iron and ascorbic acid. Dopamine behaved similarly to L-DOPA. When ascorbic acid was studied over a concentration range, LPO was stimulated at 0.5, 1, 2 or 3 mM, with or without added iron and/or dopamine; 5 and 10 mM ascorbic acid were either not as effective or suppressed LPO below control levels. Deferoxamine, a powerful iron chelator, greatly suppressed LPO under all conditions, as did diethylenetriaminepentaacetate (DTPA). Added superoxide dismutase had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipid peroxidation in brain: interactions of L-DOPA/dopamine with ascorbate and iron. 758 78

This paper examines the experimental foundations of reports in the literature on mitochondrial diseases involving Complexes I and II of the respiratory chain. Many of the reports may be questioned on the basis of the assay conditions used which disregard established knowledge of the precautions required for valid activity measurements. In addition, some findings are open to question because of the experimental material chosen for the study, such as the measurement of NADH oxidase activity in platelets in Parkinson's disease, which affects selectively the dopamine neurons, or the use of autopsy material stored for prolonged periods during which post-mortem changes may have occurred. Deficiencies claimed to involve several components of the respiratory chain may reflect indirect effects, such as defects in the synthesis of iron-sulfur clusters or in the availability of iron, rather than mutations in the genes coding for the deficient enzymes. Nevertheless, there are a few instances reported of Complex II deficiency free from such criticisms. As to Complex I, idiopathic Parkinsonism appears to involve a documentable decline in the activity of this enzyme. Using the model system provided by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces biochemical, pharmacological, and clinical syndromes closely resembling Parkinsonism, the etiology of the disease is examined.
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PMID:Deficiencies of NADH and succinate dehydrogenases in degenerative diseases and myopathies. 759 11

Neuromelanin is an amorphous pigment of the catecholamine origin that accumulates in certain dopaminergic neurons of the substantia nigra of human brain. In Parkinson's disease, there appears to be selective degeneration of the most heavily pigmented neurons of the substantia nigra, and this process has been linked to the presence of neuromelanin. It has been postulated that neuromelanin could increase the risk of oxidative stress reactions. On the other hand, melanin is usually considered to be an efficient antioxidant. Here we analyze experimental conditions that stimulate, or inhibit, antioxidant properties of neuromelanin. Using electron spin resonance (ESR)--spin trapping technique and salicylate hydroxylation assay, we monitored the formation of free hydroxyl radicals generated by a Fenton system in the presence of varying concentration of dopamine-melanin, a synthetic model for neuromelanin. Our data clearly indicate that the antioxidant action of neuromelanin is predominantly due to its ability to sequester redox-active metal ions such as iron. Using direct ESR spectroscopy, we have shown that ferric complexes with neuromelanin are resistant to reduction by mild biological reductants such as ascorbate. We have demonstrated that dopamine-melanin saturated with ferric ions, could enhance the formation of free hydroxyl radicals by redox activation of the ions. Thus, under the conditions that stimulate the release of accumulated metal ions, neuromelanin may actually become an efficient prooxidant. It is conceivable that neuromelanin, which normally is able to protect pigmented dopaminergic neurons against metal-ion related toxicity, could under extreme conditions have a cytotoxic role.
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PMID:The effect of a synthetic neuromelanin on yield of free hydroxyl radicals generated in model systems. 760 1

Oxidant-mediated damage is suspected to be involved in the pathogenesis of several neurodegenerative disorders. Iron promotes conversion of hydrogen peroxide to hydroxyl radical and, thus, may contribute to oxidant stress. We measured iron and its transport protein transferrin in caudate, putamen, globus pallidus, substantia nigra, and frontal cortex of subjects with Alzheimer's disease (n = 14) and Parkinson's disease (n = 14), and in younger adult (n = 8) and elderly (n = 8) normal controls. Although there were no differences between control groups with regard to concentrations of iron and transferrin, iron was significantly increased (p < 0.05) in Alzheimer's disease globus pallidus and frontal cortex and Parkinson's disease globus pallidus, and transferrin was significantly increased in Alzheimer's disease frontal cortex, compared with elderly controls. The transferrin/iron ratio, a measure of iron mobilization capacity, was decreased in globus pallidus and caudate in both disorders. Regional transferrin and iron concentrations were generally more highly correlated (Pearson's correlation coefficient) in elderly controls than in Alzheimer's and Parkinson's disease. The altered relationship between iron and transferrin provides further evidence that a disturbance in iron metabolism may be involved in both disorders.
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PMID:Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions. 761 27

Ferritin contains the greatest part of the iron found in the brain, and the release of iron stores from ferritin has an essential role in iron-dependent lipid peroxidation. We examined the effect of cultured microglia on iron mobilization from ferritin. Microglia stimulated by phorbol myristate acetate caused the release of iron from ferritin, which was detected by monitoring iron-ferrozine complex formation. This iron mobilization was mediated by microglial superoxide production, as evidenced by the significant inhibitory effect of superoxide dismutase. The role of superoxide was also supported by the close correspondence of cumulative microglial superoxide production, as demonstrated by the MCLA (Cypridina luciferin analogue)-dependent chemiluminescence assay, to the time course of iron release from ferritin. Iron release induced by activated microglia may be partly responsible for the oxidative damage that is thought to occur in Parkinson's disease and other neurodegenerative disorders.
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PMID:Activated microglia cause superoxide-mediated release of iron from ferritin. 762 46

Oxygen-based free radicals have been shown to play a major role in the acute destruction of neurons following cerebral ischemia and may be involved in the chronic neurodegeneration seen in Parkinson's disease, Alzheimer's disease, and other conditions characterized by the progressive death of neurons in the central nervous system. Drugs belonging to a group of antioxidant compounds, collectively known as the lazaroids, have strong neuroprotective effects in experimental models of acute ischemia. However, the specific mechanisms by which these drugs reduce the harmful actions of free radicals have not been established. Using electron paramagnetic resonance (EPR) spectroscopy with spin trapping, we investigated the interaction of U-74500A, a first-generation lazaroid, and U-78517F, a second-generation lazaroid, with two species of oxygen-based free radicals in aqueous solution and with the stable nitrogen-based free radical diphenylpicrylhydrazyl in dimethyl sulfoxide. Superoxide radicals were generated by the action of xanthine oxidase on hypoxanthine. Hydroxyl radicals were generated by the Fenton reaction involving aqueous ferrous iron and hydrogen peroxide. Both lazaroids reduce the EPR signal of all three radicals, but the drugs differ in potency and relative radical selectivity. These observations are consistent with the lazaroids being scavengers of oxygen-based and nitrogen-based free radicals and suggest that the neuroprotective actions of the lazaroids in cerebral ischemia may involve direct interactions of the lazaroids with several different species of free radicals.
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PMID:An in vitro EPR study of the free-radical scavenging actions of the lazaroid antioxidants U-74500A and U-78517F. 763 55

Free radicals are highly reactive chemical species with an unpaired electron, and their formation is catalyzed by transition metals like iron, copper, and manganese. There have been numerous studies linking free radical damage with neuropsychiatric illnesses, including several psychiatric and motor disorders, raising the possibility that antioxidant strategies might serve a neuroprotective role for some conditions. The illnesses studied include tardive dyskinesia, schizophrenia, Parkinson's disease, and Alzheimer's disease. Although oxidative mechanisms may play a role in these conditions, further studies are necessary to define their involvement, and to determine the extent to which antioxidants may partially alleviate or prevent some of these conditions.
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PMID:Free radical involvement in neuropsychiatric illnesses. 767 80


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