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)

We examined the cytotoxicity of dopa and dopamine for cultured neurons by using a newly developed enzyme immunoassay for neurofilament protein to determine surviving neuronal numbers. Each of the two catechols caused neuronal death in the presence of iron with or without superoxide dismutase and catalase, while deferoxamine mesylate prevented neuronal loss. Lipid peroxidation of phospholipid liposomes was confirmed to be produced by the combination of the catechols and iron (Fe3(+)-ADP complex). Thus, it was strongly suggested that cultured neurons were killed via the peroxidative cleavage of cell membrane components provoked by the catechols and iron. This mechanism of neuronal loss may play an important role in the degeneration in the substantia nigra of Parkinson's disease, because the catechols and iron are abundant in this region.
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PMID:Dopa and dopamine cause cultured neuronal death in the presence of iron. 190 38

Transferrin is a glycoprotein that functions primarily to deliver iron to the cell. Recent studies suggest that the transferrin receptor mediates the intracellular delivery and transport of iron bound to transferrin in the CNS. Iron-catalyzed free radical generation has been proposed as a possible cause of nigral cell death in Parkinson's disease. Our hypothesis is that abnormal iron handling by the transferrin receptor may contribute to the formation of free radical species which catalyze the lipid peroxidation of nigral cell membranes. We have assessed the number of transferrin receptors on membrane fractions prepared from the human striatum from control subjects and patients with Parkinson's disease. Equilibrium-binding studies demonstrated a reversible, saturable, and high-affinity transferrin binding site (KD = 3 nM) in human brain membranes. Regional binding assays indicate that the number of transferrin receptors in the putamen was reduced significantly in Parkinson's disease. The density of transferrin receptors was unaltered in membranes prepared from the caudate nuclei and the globus pallidus. To address the possibility that transferrin receptors are located on dopaminergic terminals, we have examined the distribution and number of transferrin receptors in the striatum of MPTP-treated mice using in vitro autoradiographic methods. In these experiments, the loss of dopaminergic terminals in the striatum was visualized by differential [3H]mazindol uptake site autoradiography. A marked reduction in the density of both transferrin receptors and [3H]mazindol binding sites was observed in the mouse striatum 7 days post-MPTP treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Distribution and number of transferrin receptors in Parkinson's disease and in MPTP-treated mice. 191 37

The vulnerability of substantia nigral (SN) melaninized dopamine neurons to neurodegeneration in Parkinson's disease and the selective increases of iron and basal lipid peroxidation in SN indicate that iron-melanin interaction could be crucial to the pathogenesis of this disease. The present study describes, for the first time, the identification and characterization of a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding site for iron on dopamine melanin. The binding of iron to melanin is dependent on pH and the concentration of melanin. Iron chelators, U74500A, desferrioxamine, and to less extent 1,10-phenanthroline and chlorpromazine, but not the Parkinson-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, can inhibit the binding of iron to melanin and iron-induced lipid peroxidation. Although melanin alone diminishes basal lipid peroxidation in rat cortical homogenates, it can also potentiate that initiated by iron, a reaction inhibited by desferrioxamine. In the absence of an identifiable exogenous or endogenous neurotoxin in idiopathic Parkinson's disease, iron-melanin interaction in pars compacta of SN may be a strong candidate for the cytotoxic component of oxygen radical-induced neurodegeneration of melaninized dopamine neurons.
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PMID:Iron-melanin interaction and lipid peroxidation: implications for Parkinson's disease. 191 77

Elevated iron concentrations in the substantia nigra (SN) pars compacta have been implicated in the development of idiopathic Parkinson's disease. Because, as a transitional metal, iron promotes free radical formation, the role of iron in the degeneration of the nigrostriatal dopamine neurons in Parkinson's disease has received much attention. This study further investigates the cytotoxic effects of iron in the SN. Various concentrations of FeCl3 (1, 5, and 50 micrograms of Fe3+ in 5 microliters) were unilaterally injected into the SN of adult rats. The two lower doses of iron had no effect on striatal dopamine levels or on the behavioral responses of the rats. However, injection of 50 micrograms of Fe3+ resulted in a substantial selective decrease of striatal dopamine (95%), 3,4-dihydroxyphenylacetic acid (82%), and homovanillic acid (45%), without any change in norepinephrine concentration. Dopamine-related behavioral responses, such as spontaneous movements in a novel space and rearing, were significantly impaired, whereas amphetamine administration induced ipsilateral rotation in the iron-treated rats. The present study indicates that the nigrostriatal dopamine neurons are susceptible to the presence of ionic iron and thus supports the assumption that iron initiates dopaminergic neurodegeneration in Parkinson's disease.
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PMID:Intranigral iron injection induces behavioral and biochemical "parkinsonism" in rats. 194 Sep 19

The levels of different elements were studied by x-ray microanalysis in the substantia nigra and the central gray substance of patients with Parkinson's disease, progressive supranuclear palsy, and matched controls. In control brains, only iron, potassium, silicum, sodium, sulfur, and zinc were within the limit of detection of the technique. The abundance of each element was different, but their respective concentrations in the two brain regions were similar, except for sulfur levels which were higher on neuromelanin aggregates in the substantia nigra than in nigral regions lacking neuromelanin, and in the central gray substance. In Parkinson's disease, but not in progressive supranuclear palsy, nigral iron levels increased in regions devoid of neuromelanin and decreased on neuromelanin aggregates, but were unchanged in the central gray substance, when compared to control values. Concentrations of the other elements in the central gray substance and substantia nigra were not different from controls in brains from patients with Parkinson's disease and progressive supranuclear palsy. Analysis of Lewy bodies in the parkinsonian substantia nigra revealed high levels of iron and the presence of aluminum. Metal abundance was not affected in progressive supranuclear palsy, in spite of the nigral cell death. This suggests that the increased iron levels and the detection of aluminum observed in Parkinson's disease are not solely the consequence of the neuronal degeneration.
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PMID:Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: an X-ray microanalysis. 198 48

The involvement of oxygen radicals in the pathogenesis of Parkinson's disease has been suggested for some time. This article reviews the evidence supporting the involvement of oxygen radicals in the disease process in the brain. This includes a discussion of iron, lipid peroxidation, peroxidase, catalase, superoxide dismutase, and glutathione levels in the brain. In addition, various theories of induction of Parkinson's disease are discussed in relation to the possible involvement of oxygen radicals. These theories include the environmental toxin theory, the dopamine turnover theory, and the cerebral blood flow theory.
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PMID:Oxygen free radicals and Parkinson's disease. 201 74

Recent evidence suggests that iron accumulates in substantia nigra pars compacta of patients with Parkinson's disease (PD). This finding is compatible with changes in the respiratory chain activity, increase of malondialdehyde concentration (a measure of lipid peroxidation), decrease of enzyme activity of enzymes involved in detoxication of hydrogen peroxide and oxygen radical species, increased MAO-B-activity in this brain area etc. All these data suggest that oxidative stress may play a certain role in the pathobiochemistry of PD. In addition to the description of the neuroprotective mechanism of the MAO-B-inhibitor L-deprenyl a new aspect focuses the role of the endogenous MAO-B substrates "polyamines" which occur both in neurons and glia. A further aspect of this review deals with the role of calcium as cellular toxin. Although of major importance it is not decided yet whether these biochemical changes are primary or secondary importance to the pathogenesis of PD.
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PMID:The role of monoamine oxidase, iron-melanin interaction, and intracellular calcium in Parkinson's disease. 208 94

Although many authors have suggested that dopamine and its metabolites producing free radicals have an harmful effect in the substantia nigra, experimental evidence has not been shown. Using a newly established enzyme immunoassay of the neurofilament protein, a reliable index for the number of survived neurons in tissue culture, we evaluate the effects of Dopa on the neurons of dorsal root ganglia from mice. Neurons were destroyed by the exposure of 0.5 mM Dopa with or without superoxide dismutase and catalase, but they were saved by the pretreatment with 1.0 mM deferoxamine mesylate, a powerful iron-chelating agent. Formation of malondialdehyde, an index of lipid peroxidation, was also observed in the reaction of 0.5 mM Dopa and cerebral cortical neurons from new-born rats only when iron was present. These results indicate that Dopa initiates lipid peroxidation of cell membrane in the presence of a small amount of iron in the culture with little or no participation of reactive oxygen species, leading to the destruction of the neurons. In Parkinson's disease, the cytotoxic mechanism of Dopa and iron may involve the neuronal degeneration in the substantia nigra abundant in iron and dopaminergic neurons.
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PMID:[Iron-dependent cytotoxic effects of dopa on cultured neurons of the dorsal root ganglia]. 211 13

The degeneration of nigro-striatal dopaminergic neurons is considered to be a predominant pathogenetic factor of Parkinson's disease (PD). However, the etiology of this degeneration is not known. Hypotheses assume accumulation of endogenous and/or exogenous toxins as trigger of the disease. An increase in the concentration of free radicals has been suggested to be toxic to cells, especially when combined with certain metals like free iron or copper. The role of melanin in the degenerative process is not clear, but autoxidative reactions such as the oxidation of dopamine (DA) to melanin generating radicals and toxic metabolites seem to enhance the vulnerability of neurons in the substantia nigra (SN). Disappearance of melanin in the SN, increase of total iron and ferric iron, extreme decrease of glutathione (GSH) levels, reduced activity of enzymes involved in the detoxification of hydrogen peroxide, hydroxyl and superoxide radicals (peroxidases, catalase, glutathione peroxidase), an increase of monoamine oxidase B (MAO B) activity and the substantial increase of malondialdehyde, a marker of lipid peroxidation, in the SN seem to indicate a role of an oxidative stress syndrome in the SN causing or aggravating PD.
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PMID:Oxidative stress: a role in the pathogenesis of Parkinson's disease. 219 8

The recent studies on the chemical pathology of Parkinson's disease show selective increases of iron and lipid peroxidation and decreased glutathione (GSH) oxidizing capacity in the substantia nigra (SN). These changes are indicative of oxidative stress, possibly due to the accumulation of iron in the SN. It is the melaninized dopamine neurons that are vunerable to degeneration. The investigation of the interaction of iron with dopamine melanin demonstrates the presence of two relatively high affinity binding sites for 59Fe3+ on dopamine melanin. Interaction of Fe3+ with dopamine melanin results in potentiation of lipid peroxidation of rat cerebral cortex as compared to that induced by Fe3+. Only compounds with the ability to chelate iron are able to inhibit the binding of Fe3+ to melanin and the resultant lipid peroxidation. Therapeutic use of iron chelators, with the ability of crossing the blood brain barrier, as agents for retarding the oxidative stress and Parkinson's disease is envisaged.
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PMID:Selectivity of melaninized nigra-striatal dopamine neurons to degeneration in Parkinson's disease may depend on iron-melanin interaction. 219 9


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