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)

Increasing knowledge of the role of brain iron in health and disease has prompted consideration of therapeutic strategies aimed at attenuating the effects of iron and its untoward oxidative consequences. The success of this approach is critically dependent on a better understanding of the pathogenesis of Parkinson's disease. The controlled trial "Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism" (DATATOP) represents a clinical strategy to detect neuroprotective effects of antioxidative interventions. Validation of reliable biological markers of nigral degeneration is central to development of therapies that exert genuine neuroprotective effects in slowing the progression and preventing the onset of Parkinson's disease.
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PMID:Neuroprotective clinical strategies for Parkinson's disease. 151 Mar 74

Iron-induced oxidant stress has been implicated in the pathogenesis of Parkinson's disease. An increasing body of evidence now indicates that in Parkinson's disease the environment within the substantia nigra is conducive to the formation of cytotoxic free radicals and cell degeneration. Dopamine neurons may be particularly vulnerable because of the oxidative metabolism of dopamine and the potential of neuromelanin to promote the site-specific accumulation and reduction of iron. This hypothesis has attracted considerable attention because it opens the way for employing antioxidant strategies as possible neuroprotective treatment for Parkinson's disease. Although the concept is appealing, free radicals have not yet been proven to play a role in Parkinson's disease, and many important issues remain to be resolved before the oxidative hypothesis can ultimately be confirmed or refuted.
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PMID:An introduction to the free radical hypothesis in Parkinson's disease. 151 Mar 76

We examine the evidence for free radical involvement and oxidative stress in the pathological process underlying Parkinson's disease, from postmortem brain tissue. The concept of free radical involvement is supported by enhanced basal lipid peroxidation in substantia nigra in patients with Parkinson's disease, demonstrated by increased levels of malondialdehyde and lipid hydroperoxides. The activity of many of the protective mechanisms against oxidative stress does not seem to be significantly altered in the nigra in Parkinson's disease. Thus, activities of catalase and glutathione peroxidase are more or less unchanged, as are concentrations of vitamin C and vitamin E. The activity of mitochondrial superoxide dismutase and the levels of the antioxidant ion zinc are, however, increased, which may reflect oxidative stress in substantia nigra. Levels of reduced glutathione are decreased in nigra in Parkinson's disease; this decrease does not occur in other brain areas or in other neurodegenerative illnesses affecting this brain region (i.e., multiple system atrophy, progressive supranuclear palsy). Altered glutathione metabolism may prevent inactivation of hydrogen peroxide and enhance formation of toxic hydroxyl radicals. In brain material from patients with incidental Lewy body disease (presymptomatic Parkinson's disease), there is no evidence for alterations in iron metabolism and no significant change in mitochondrial complex I function. The levels of reduced glutathione in substantia nigra, however, are reduced to the same extent as in advanced Parkinson's disease. These data suggest that changes in glutathione function are an early component of the pathological process of Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson's Disease Research Group. 151 Mar 85

Although the cause of neuronal death in Parkinson's disease remains unknown, a hyperoxidation phenomenon has been implicated as a potential cytotoxic mechanism. Catecholaminergic neurons containing neuromelanin, an autoxidation byproduct of catecholamines, are more vulnerable in Parkinson's disease than nonmelanized catecholaminergic neurons. High levels of CuZn superoxide dismutase mRNA have been observed in the substantia nigra, suggesting that high levels of oxygen free radicals are indeed produced in the structure. Catecholaminergic neurons surrounded by a low density of glutathione peroxidase cells are more susceptible to degeneration in Parkinson's disease than those well protected against oxidative stress. The nigral content in iron, a compound that exacerbates the production of free radicals in catecholaminergic neurons, is increased in Parkinson's disease. Altogether these data suggest that hyperoxidation may participate in the selective vulnerability of catecholaminergic neurons in Parkinson's disease.
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PMID:Why are nigral catecholaminergic neurons more vulnerable than other cells in Parkinson's disease? 151 Mar 86

Previously we have shown that cell death in the substantia nigra (SN) in Parkinson's disease (PD) is associated with an increase in iron content but a decrease in the level of the iron-binding protein ferritin. Alterations in other metal ion levels were also observed; copper levels were reduced, whereas zinc levels were increased. The importance of these changes in iron, ferritin, and other metal ions in the pathophysiology of PD depends on whether they are specific to the illness. We measured levels of iron, copper, zinc, manganese, and ferritin in postmortem tissue from patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (which shows pathology in the SN and striatum) and Huntington's disease (HD) (which shows pathological changes in the striatum, compared with control subjects). Total iron levels were elevated in areas of the basal ganglia showing pathological changes in these disorders. In particular, total iron content was increased in SN in PD, PSP, and MSA, but not in HD. Total iron levels in the striatum (caudate nucleus and/or putamen) were increased in PSP, MSA, and HD, but not in PD. There were no consistent alterations in manganese levels in the basal ganglia in any of the diseases studied. Copper levels were decreased in the SN in PD and in the cerebellum in PSP, and were elevated in the putamen and possibly the SN in HD. Zinc levels were only increased in PD in the SN, the caudate nucleus, and the putamen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson's Disease Research Group. 151 Mar 87

The detailed anatomical distribution of iron in the post-mortem human brain has been studied using Perl's and Turnbull's methods with the diaminobenzidine intensification procedure for the demonstration of non-haem Fe3+ and Fe2+, respectively. Attention to methodological procedures has revealed that even brief immersion of tissue in routinely used fixatives causes a reduction of staining intensity in areas of high iron content and, often, loss of staining in areas of low iron content. Optimal staining is obtained using frozen section briefly fixed for 5 min in 4% formalin and Perl's stain (Fe3+) with diaminobenzidine intensification. Highest levels of stainable iron were found in the extrapyramidal system with the globus pallidus, substantia nigra zona reticulata, red nucleus and myelinated fibres of the putamen showing highest staining reactivity. Moderate staining intensity with Perl's technique was found in the majority of forebrain, midbrain and cerebellar structures with the striatum, thalamus, cortex and deep white matter, substantia nigra zona compacta, and cerebellar cortex showing consistent staining patterns with intensification of Perl's stain. The brain-stem and spinal cord generally only showed staining with the intensification procedure and even this was of low intensity. Microscopically the non-heam iron appears to be found predominantly in glial cells as fine cytoplasmic granules which in heavily stained areas coalesce to fill the entire cell. Iron-positive granules appear to be free in the neuropil and also around blood vessels in the globus pallidus, striatum and substantia nigra. The neuropil shows a fibrous impregnation when stained for iron which is, in part, derived from glial processes, myelinated fibres and fibre bundles. Neurones, in general, show only very low reactivity for iron, and this is difficult to discern due, often, to the higher reactivity of the surrounding neuropil. In the globus pallidus and substantia nigra zona reticulata, neurones with highly stainable iron content are found with granular cytoplasmic iron reactivity similar to that seen in the local glial cells. Our results are comparable with those of early workers, but with the use of intensification extend the distribution of non-haem iron to areas previously reported as negative. No apparent correlation of iron staining with known neurotransmitter systems is seen and the predilection for the extrapyramidal system is not easily explained, though the non-haem iron in the brain appears to be as a storage form in the iron storage protein ferritin. The localization of iron in the brain provides a foundation for the study of iron in certain neurodegenerative diseases such as Parkinson's disease, where iron has been implicated in the pathogenesis.
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PMID:Histochemical distribution of non-haem iron in the human brain. 152 78

Studies have shown that severe daytime restriction of dietary protein improves the efficacy of L-dopa and reduces response fluctuations in some Parkinson's disease (PD) patients. This study investigated the nutritional adequacy of the daytime restricted-protein diet. Eleven free-living PD patients suffering from unpredictable response fluctuations to L-dopa were counseled to limit protein intake to approximately 10 g before 1700. Three sets of 6-d food records obtained during the 8-wk study showed that while on the test diet, mean intakes of most nutrients remained above the recommended nutrient intakes, although significant decreases occurred in protein, calcium, iron, phosphorus, riboflavin, and niacin intakes. The impact of the test diet on nutritional status as evaluated by changes in body weight and serum prealbumin was small. We conclude that healthy and highly motivated patients can maintain adequate intakes of most nutrients while restricting daytime protein intake. However, nutrient intakes might be compromised in patients whose regular diets are marginally adequate.
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PMID:Effect of daytime protein restriction on nutrient intakes of free-living Parkinson's disease patients. 155 46

The action of toxins or the altered metabolism of dopamine may lead to oxidative stress in substantia nigra, thereby inducing dopamine cell death and the onset of Parkinson's disease. Postmortem studies showing a depletion of reduced glutathione and increased mitochondrial superoxide dismutase activity suggest the occurrence of an ongoing toxic process in substantia nigra involving free radical mechanisms. Indeed there is a selective impairment of complex I of the mitochondrial respiratory chain in substantia nigra in Parkinson's disease, mimicking the mode of action of the selective nigral toxin MPTP. The increased formation of free radical species in substantia nigra in patients with Parkinson's disease may be accelerated by an accumulation of iron within this brain region. Altered iron metabolism and impaired mitochondrial function are not apparent in the early stages of the illness and therefore may act as accelerators of some other primary pathologic process.
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PMID:What process causes nigral cell death in Parkinson's disease? 158 81

MRI is a relatively simple, safe, in vivo technique that has proved to be of great value in differentiating patients with Parkinson's disease from those with atypical parkinsonism, and it is the first laboratory marker to be able to do so. By permitting the in vivo detection of increased iron in the nigra and striatum of patients with parkinsonism, MRI may also have provided a clue into the mechanism of cell death in neurodegenerative disorders. Finally it is conceivable that MRI scanning may serve as a screening tool that permits the early recognition of pathologic iron accumulation before the development of clinical symptoms. This is reasonable to anticipate for patients with atypical parkinsonism in whom large quantities of iron appear to accumulate in the putamen early in the disease. It is possible that with some refinement, abnormalities in the nigra may be detected on MRI with a higher level of certainty. In an era in which we may be able to provide neuroprotective therapy, MRI might be an important technique for defining a population of patients at risk for the development of Parkinson's disease who might benefit from presymptomatic therapy.
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PMID:Magnetic resonance imaging in parkinsonism. 158 82

Iron, a transition metal possibly involved in the pathogenesis of Parkinson's disease, was tested for its toxic effects toward cultures of dissociated rat mesencephalic cells. When cultures were switched for 24 h to serum-free conditions, the effective concentrations of ferrous iron (Fe2+) producing a loss of 50% of dopaminergic neurons, as quantified by tyrosine hydroxylase (TH) immunocytochemistry, TH mRNA in situ hybridization, and measurement of TH activity, were on the order of 200 microM. High-affinity dopamine (DA) uptake, which reflects integrity and function of dopaminergic nerve terminals, was impaired at significantly lower concentrations (EC50 = 67 microM). Toxic effects were not restricted to dopaminergic neurons inasmuch as trypan blue dye exclusion index and gamma-aminobutyric acid uptake, two parameters used to assess survival of other types of cells present in these cultures, were also affected. Protection against iron cytotoxicity was afforded by desferrioxamine and apotransferrin, two ferric iron-chelating agents. Normal supplementation of the culture medium by serum proteins during treatment was also effective, presumably via nonspecific sequestration. Potential interactions with DA were also investigated. Fe2+ at subtoxic concentrations and desferrioxamine in the absence of exogenous iron added to the cultures failed to potentiate or reduce DA cytotoxicity for mesencephalic cells, respectively. Transferrin, the glycoprotein responsible for intracellular delivery of iron, was ineffective in initiating selective cytotoxic effects toward dopaminergic neurons preloaded with DA. Altogether, these results suggest (a) that ferrous iron is a potent neurotoxin for dopaminergic neurons as well as for other cell types in dissociated mesencephalic cultures, acting likely via autoxidation into its ferric form, and (b) that the presence of intra- and extracellular DA is not required for the observed toxic effects.
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PMID:Toxic effects of iron for cultured mesencephalic dopaminergic neurons derived from rat embryonic brains. 161 93


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