Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Occupational and environmental exposure to manganese (Mn(2+)) is an increasing problem. It manifests neuronal degeneration characterized by dyskinesia resembling Parkinson's disease. The study was performed to test the hypotheses whether exposure to Mn(2+) alters cellular physiology and promotes intracellular signaling mechanism in dopaminergic neuronal cell line. Since transcription factors have been shown to play an essential role in the control of cellular proliferation and survival, catecholaminergic rich pheochromocytoma (PC12) cells were used to measure changes in the DNA binding activities of nuclear factor kappa B (NF-kappaB) by electrophoretic mobility shift assay (EMSA) following Mn(2+) (0.1-10 microM) exposure. Cells that were exposed to Mn(2+) produced five-fold-activation of transcription factor NF-kappaB DNA binding activity. This remarkable increase was seen within 30-60 min period of Mn(2+) exposure. Activation of NF-kappaB DNA binding activity by Mn(2+) at 1.0 microM correlated with proteolytic degradation of the inhibitory subunit IkappaB(alpha) as evidenced in cytosol. Additional experiments on NF-kappaB reporter gene assay also showed increased NF-kappaB gene expression at 1.0 and 5.0 microM Mn(2+) and this was completely blocked in the presence of NF-kappaB translocation inhibitor, IkappaB(alpha)-DN supporting that NF-kappaB induction occurred during Mn(2+) exposure. In addition, Mn(2+) exposure to PC 12 cells led to activation of signal responsive mitogen activated protein kinase kinase (MAPKK). These results suggest that Mn(2+) at a low dose appears to induce the expression of immediate early gene, NF-kappaB through MAPKK by a mechanism in which IkappaB(alpha) phosphorylation may be involved.
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PMID:Activation of early signaling transcription factor, NF-kappaB following low-level manganese exposure. 1242 65

The human central nervous system is an important target for manganese intoxication, which causes neurological symptoms similar to those of Parkinson's disease. With the increasing use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-improving additive to unleaded gasoline, the prospect of worldwide manganese exposure is once again attracting attention as increases in environmental manganese concentrations have been recorded relative to traffic density. One crucial question is whether a small increase of manganese contamination resulting from the widespread use of MMT could have neurotoxic effects. In this review we concentrate on central nervous system abnormalities and neurobehavioral disturbances. Most experimental animal studies on manganese neurotoxicity have been conducted in nonhuman primates and rodents. Most studies performed in rodents used oral manganese administration and did not assess bioaccumulation or central nervous system changes. The major effect found was transient modification of spontaneous motor activity. Very few inhalation toxicological studies were carried out. As manganese intoxication in humans usually occurs via inhalation, more studies are required using the respiratory route of administration. Given the proven neurotoxic effects of manganese and the prospect of worldwide MMT usage, this metal should be considered a new environmental pollutant having potentially widespread public health consequences.
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PMID:Manganese neurotoxicity: behavioral, pathological, and biochemical effects following various routes of exposure. 1246 83

The spectrum of movement disorders in the tropics is different from that seen in the industrialized nations of the west. This is not surprising given the unique combination of environmental and population characteristics in the tropics. Infections seldom encountered in the west such as tuberculous meningitis, typhoid fever, Japanese encephalitis, malaria, trypanosomiasis or cysticercosis are often seen in the tropics and with global patterns of travel and immigration these conditions are becoming more common worldwide. Movement disorders associated with these infections, HIV, slow virus and prion disease are discussed. Taking into account the diverse etiologies of movement disorders in the tropics, movement disorders with a nutritional basis such as the infantile tremor syndrome, seasonal ataxia and tropical ataxic neuropathy, and manganese neurotoxicity are also reviewed. Finally, certain special characteristics of ubiquitous disorders such as Parkinson's disease, and disorders with a genetic basis such as Wilson's disease and spinocerebellar degeneration are described.
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PMID:Movement disorders in the tropics. 1247 95

Dithiocarbamate (DTC)-based pesticides have been implicated in Parkinson's disease (PD) through epidemiological links to increased risk of PD, clinical reports of parkinsonism following occupational exposure to the DTC-based pesticide maneb, and experimental studies showing dopaminergic neurodegeneration with combined exposure of rats to maneb and paraquat. We hypothesize that the manganese-ethylene-bis-dithiocarbamate (MnEBDC) complex in maneb may produce oxidative stress by catalyzing catechol oxidation. We tested this hypothesis by performing a structure-function analysis of metal-EBDC and metal-diethyldithiocarbamate (DEDC) complexes of Mn2+, Zn2+, and Cu2+ to catalyze oxidation of N-acetyldopamine (NA-DA) and 3,4-dihydroxyphenylacetic acid (DP) in the presence and absence of N-acetylcysteine (NAC), a model of glutathione. Both Mn-DTCs retained the capacity of the parent ion to catalyze one-electron oxidation of NA-DA, but lost the ability to catalyze DP oxidation. Strikingly, while Zn2+ did not catalyze catechol oxidation, both Zn-DTCs catalyzed one-electron oxidation of NA-DA but not DP. While Cu2+ catalyzed oxidation of both catechols, Cu-DTCs were inert. Similar results were obtained with MnEBDC and dopamine or norepinephrine; however, zinc-ethylene-bis-dithiocarbamate was less efficient at catalyzing oxidation of these catechols. Our results point to the potential for manganese- and zinc-containing EBDC pesticides to promote oxidative stress in catecholaminergic regions of the brain.
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PMID:Catalysis of catechol oxidation by metal-dithiocarbamate complexes in pesticides. 1248 39

Manganese, an essential trace metal, is supplied to the brain via both the blood-brain and the blood-cerebrospinal fluid barriers. There are some mechanisms in this process and transferrin may be involved in manganese transport into the brain. A large portion of manganese is bound to manganese metalloproteins, especially glutamine synthetase in astrocytes. A portion of manganese probably exists in the synaptic vesicles in glutamatergic neurons and the manganese is dynamically coupled to the electrophysiological activity of the neurons. Manganese released into the synaptic cleft may influence synaptic neurotransmission. Dietary manganese deficiency, which may enhance susceptibility to epileptic functions, appears to affect manganese homeostasis in the brain, probably followed by alteration of neural activity. On the other hand, manganese also acts as a toxicant to the brain because this metal has prooxidant activity. Abnormal concentrations of manganese in the brain, especially in the basal ganglia, are associated with neurological disorders similar to Parkinson's disease. Understanding the movement and action of manganese in synapses may be important to clarify the function and toxicity of manganese in the brain.
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PMID:Manganese action in brain function. 1250 49

Endogenous or exogenous substances that are toxic to dopaminergic cells have been proposed as possible cause of idiopathic Parkinson's disease (PD). 1-Methyl-4-phenylpyridinium (MPP(+)) and manganese are dopaminergic neurotoxins causing a parkinsonism-like syndrome. Here, we studied the possible synergistic reaction between these two neurotoxins using rat PC12 pheochromocytoma cells. MPP(+) induced a delayed neurotoxicity in PC12 cells. Although low concentration of manganese did not cause cell damage, it markedly enhanced MPP(+)-induced neurotoxicity with characteristics of apoptosis, such as DNA laddering and activation of caspase-3. To understand the mechanism of enhancement of subtoxic concentration of manganese on MPP(+)-induced neurotoxicity, we investigated the reactive oxygen species (ROS) generation using a molecular probe, 2',7'-dichlorofluorescein diacetate. Although subtoxic concentration of manganese alone did not induce ROS increase, it significantly enhanced the ROS generation induced by MPP(+). We also determined the intracellular MPP(+) content. A time- and concentration-dependent increase of MPP(+) levels was found in PC12 cells treated with MPP(+). The accumulation of MPP(+) by PC12 cells was not affected by manganese. Taken together, these studies suggest that co-treatment with MPP(+) and manganese may induce synergistic neurotoxicity in PC12 cells and that subtoxic concentration of manganese may potentiate the effect of MPP(+) by an ROS-dependent pathway.
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PMID:Subtoxic concentration of manganese synergistically potentiates 1-methyl-4-phenylpyridinium-induced neurotoxicity in PC12 cells. 1253 85

Manganese ethylene-bis-dithiocarbamate (Mn-EBDC) is the major active element of maneb, a pesticide linked to parkinsonism in certain individuals upon chronic exposure. Additionally, it has been shown to produce dopaminergic neurodegeneration in mice systemically coexposed to another pesticide, 1,1'-dimethyl-4,4'-bipyridinium (paraquat). Here, we described a rat model in which selective dopaminergic neurodegeneration was produced by delivering Mn-EBDC directly to the lateral ventricles. After establishing this model, we tested whether Mn-EBDC provoked dopamine efflux in the striatum, a well-known phenomenon produced by the mitochondrial inhibitor 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that causes parkinsonism in humans, as well as in some animals. Finally, we investigated whether Mn-EBDC directly inhibited mitochondrial function in vitro using isolated brain mitochondria. Our data demonstrated that Mn-EBDC induced extensive striatal dopamine efflux that was comparable with that induced by MPP+, and that Mn-EBDC preferentially inhibited mitochondrial complex III. As mitochondrial dysfunction is pivotal in the pathogenesis of Parkinson's disease (PD), our results support the proposal that exposure to pesticides such as maneb, or other naturally occurring compounds that inhibit mitochondrial function, may contribute to PD development.
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PMID:Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction. 1255 96

The central nervous system, and the basal ganglia in particular, is an important target in manganese neurotoxicity, a disorder producing neurological symptoms similar to that of Parkinson's disease. Increasing evidence suggests that astrocytes are a site of early dysfunction and damage; chronic exposure to manganese leads to selective dopaminergic dysfunction, neuronal loss, and gliosis in basal ganglia structures together with characteristic astrocytic changes known as Alzheimer type II astrocytosis. Astrocytes possess a high affinity, high capacity, specific transport system for manganese facilitating its uptake, and sequestration in mitochondria, leading to a disruption of oxidative phosphorylation. In addition, manganese causes a number of other functional changes in astrocytes including an impairment of glutamate transport, alterations of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, production of nitric oxide, and increased densities of binding sites for the "peripheral-type" benzodiazepine receptor (a class of receptor predominantly localized to mitochondria of astrocytes and involved in oxidative metabolism, mitochondrial proliferation, and neurosteroid synthesis). Such effects can lead to compromised energy metabolism, resulting in altered cellular morphology, production of reactive oxygen species, and increased extracellular glutamate concentration. These consequences may result in impaired astrocytic-neuronal interactions and play a major role in the pathophysiology of manganese neurotoxicity.
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PMID:Manganese neurotoxicity: an update of pathophysiologic mechanisms. 1260 14

Chronic exposure to the divalent heavy metals, such as iron, lead, manganese (Mn), and chromium, has been linked to the development of severe, often irreversible neurological disorders and increased vulnerability to developing Parkinson's disease. Although the mechanisms by which these metals elicit or facilitate neuronal cell death are not well defined, neurotoxicity is limited by the extent to which they are transported across the blood-brain barrier and their subsequent uptake within targeted neurons. Once inside the neuron, these heavy metals provoke a series of biochemical and molecular events leading to cell death induced by either apoptosis and/or necrosis. The toxicological properties of Mn have been studied extensively in recent years because of the potential health risk created by increased atmospheric levels owing to the impending use of the gas additive methylcyclopentadienyl manganese tricarbonyl. Individuals exposed to high environmental levels of Mn, which include miners, welders, and those living near ferroalloy processing plants, display a syndrome known as manganism, best characterized by debilitating symptoms resembling those of Parkinson's disease. Mn disposition in vivo is influenced by dietary iron intake and stores within the body since the two metals compete for the same binding protein in serum (transferrin) and subsequent transport systems (divalent metal transporter, DMT1). There appear to be two distinct carrier-mediated transport systems for Mn and ferrous ion: a transferrin-dependent and a transferrin-independent pathway, both of which utilize DMT1 as the transport protein. Accordingly, this commentary focuses on the biochemical and molecular processes responsible for the cytotoxic actions of Mn and the role that cellular transport plays in mediating the physiological as well as the toxicological actions of this metal.
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PMID:Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese. 1281 60

Manganese, which enters the body primarily via inhalation, can damage the nervous system and respiratory tract, as well as have other adverse effects. Occupational exposures occur mainly in mining, alloy production, processing, ferro-manganese operations, welding, and work with agrochemicals. Among the neurologic effects is an irreversible parkinsonian-like syndrome. An estimated 500,000 to 1.5 million people in the United States have Parkinson's disease, and physicians need to consider manganese exposure in its differential diagnosis. Since 1837, there have been many reports of cases and case series describing manganese toxicity. More recently, there have been epidemiologic studies of its adverse effects on health. Occupational medicine physicians can play critical roles in preventing the adverse health effects of manganese.
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PMID:Neurologic effects of manganese in humans: a review. 1284 44


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