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)

Age-related human neurodegenerative diseases are a major social and medical problem. It is therefore logical to take into consideration every theory with an overall approach to neurodegenerative diseases. This environmental proposal relies mainly on data concerning the Western Pacific amyotrophic lateral sclerosis-Parkinsonism-dementia complex (WP ALS-PD) considered as 'a prototypal human neurodegenerative disease' and on extrapolation from it to the bulk of neurodegenerative diseases (NDD). NDD would be due to an accelerated ageing process in certain populations of neurons due to the noxious synergy of (1) increased environmental slow deleterious factors (such as slow toxins) and of (2) decreased environmental protective factors (Mg deficient intake particularly). First, it was observed that three apparently dissimilar conditions occurred at extraordinary high rates in the Guam area: motoneuron disease (ALS), Parkinson's disease (P) and Alzheimer's-like dementia (D). Next, several other foci of endemic ALS-PD were found in Asia and Oceania in three Western Pacific population groups. These included the Chamorro people in Mariana Islands (Guam and Rota), the Auyu and Jakai people of West New Guinea and the Japanese residents of the Kii peninsula (Honshu island). The post-Second World War decline of the occurrence of WP ALS-PD in all three high incidence disease foci coupled with the absence of demonstrable heritable or transmissible factors had led to focus the search for the cause of this degenerative disease on nontransmissible environmental factors that are disappearing as the susceptible population groups acculturate to modern way. Epidemiologic study has shown that preference for traditional Chamorro food is the only one of 23 tested variables significantly associated with an increased risk for PD. An early suggestion incriminated the toxic seed of the false sago palm (Cycas circinalis L) which was used in traditional food and medicine. Laboratory investigation of cycad seed revealed the presence of various toxins and particularly of an 'unusual' non protein aminoacid: L-BMAA (beta-N-methylamino-L-alanine), an excitotoxic aminoacid. This slow toxin presents some structural similarity to another 'unusual' excitotoxic aminoacid: L-BOAA (beta-N-oxalyl-amino-L-alanine), an exogenous neurotoxin present in the grass pea (Lathyrus sativus) whose excessive consumption may cause lathyrism. The excitotoxicity of both L-BMAA and L-BOAA mainly concerns non-NMDA receptors. The neurotoxicity of these aminoacids varies with experimental models failing to induce an experimental model akin to WP ALS-PD or displaying many of the motor-system and behavioral changes of WP ALS-PD. It may be due to the presence of physiological levels of bicarbonate or of various toxic cofactors: bio-organic such as cycasin or inorganic such as pollutant metals e.g. aluminum or manganese, together with the lack of protective factors (e.g. calcium and magnesium deficiencies). Combined Al intoxication with Ca-Mg deficiencies is a reasonable model to investigate the pathogenesis of neurodegenerative diseases and eventually to screen their treatments. It may also be considered as a model of magnesium deficit, but it does not concern simple magnesium deficiency reversible with mere oral physiological magnesium supplementation. Magnesium deficiency cannot result in neurodegenerative disease. Combined Al intoxication with Ca-Mg deficiencies is not reversible through physiological oral magnesium supplementation. It therefore constitutes a type of experimental magnesium depletion model, instrumental in the investigation of the pathogenesis of magnesium depletion and in the screening of its still unknown possible treatments. (ABSTRACT TRUNCATED)
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PMID:Are age-related neurodegenerative diseases linked with various types of magnesium depletion? 951 30

We studied the long-term clinical course of five patients with chronic manganese intoxication. The mean scores of the King's College Hospital Rating Scale for Parkinson's disease increased from 15.0 +/- 4.2 in 1987 to 28.3 +/- 6.70 in 1991 and then to 38.1 +/- 12.9 in 1995. The deterioration was most prominent in gait, rigidity, speed of foot tapping, and writing. Tissue concentrations of manganese in blood, urine, scalp hair, and pubic hair returned to normal. Follow-up MRIs did not show paramagnetic high-signal intensity on T1-weighted images. The data indicate that clinical progression in patients with manganese parkinsonism continues even 10 years after cessation of exposure.
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PMID:Long-term progression in chronic manganism: ten years of follow-up. 952 Dec 59

Iron(II/III) and manganese(II) both catalyze the autoxidation of the neurotransmitter dopamine (DA) in the presence of L-cysteine (CySH) in buffered aqueous solution at pH 7.4. Fe2+/Fe3+ and CySH together generate the hydroxyl (HO.) and cysteinyl thiyl (CyS.) radicals. DA is oxidized by HO. to DA semiquinone radical species that either react with CyS. to give 5-S-cysteinyldopamine (5-S-CyS-DA), 2-S-CyS-DA, and 6-S-CyS-DA or disproportionate to DA-o-quinone that reacts with CySH to give the same cysteinyl conjugates of DA. The major product of this initial reaction is 5-S-CyS-DA. However, 5-S-CyS-DA can be further oxidized by HO. to an o-quinone (2) that undergoes intramolecular cyclization to an o-quinone imine (3). The latter intermediate is the precursor of the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-1) and several other cyclized products. However, cysteinyl conjugates of DA can also be oxidized by HO. in a one-electron abstraction reaction that leads to DA thiyl radicals. Reactions of these radicals with CyS. or DA semiquinone radicals lead to some novel DA disulfides and thioethers, respectively. The Mn(II)-catalyzed oxidation of DA generates DA-o-quinone that is scavenged by CySH to give 5-S-CyS-DA (major initial product) with lower yields of other cysteinyldopamines. Subsequent Mn(II)-catalyzed oxidation of 5-S-CyS-DA gives o-quinone 2 and thence o-quinone imine 3 that serve as the precursors of DHBT-1 and several other DHBTs. Organic or oxygen radicals do not play significant roles in the Mn(II)-catalyzed oxidation of DA in the presence of CySH. Recent studies have demonstrated that DHBT-1 can be accumulated by brain mitochondria and evoke irreversible inhibition of NADH-coenzyme Q reductase (complex I). Furthermore, iron, manganese, and alterations in glutathione and CySH metabolism have been implicated in the selective degeneration of nigrostriatal dopaminergic neurons in idiopathic and chemically induced Parkinson's disease (PD). Because DHBT-1 is formed in both the iron- and manganese-catalyzed oxidation of DA in the presence of CySH and a defect in mitochondrial complex I respiration contributes to dopaminergic neuronal cell death in PD, the results of this investigation are discussed in terms of their possible implications to an understanding of the neuropathological processes in idiopathic and chemically induced parkinsonism.
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PMID:Iron- and manganese-catalyzed autoxidation of dopamine in the presence of L-cysteine: possible insights into iron- and manganese-mediated dopaminergic neurotoxicity. 967 46

It has been suggested that transition metals such as iron and manganese produce oxidative injury to the dopaminergic nigrostriatal system. which may play a critical role in the pathogenesis of Parkinson's disease. Intranigral infusion of ferrous citrate (0 to 8.4 nmol, i.n.) acutely increased lipid peroxidation in the substantia nigra and dopamine turnover in the caudate nucleus. Subsequently, it caused a severe depletion of dopamine levels in the rat caudate nucleus. In contrast to iron's pro-oxidant effect, manganese (up to 30 nmol, i.n.) causes neither lipid peroxidation nor nigral injury/dopamine depletion. Manganese (1.05 to 4.2 nmol, i.n.) dose-dependently protected nigral neurons from iron-induced oxidative injury and dopamine depletion. Manganese also suppressed acute increase in dopamine turnover and contralateral turning behaviour induced by iron. In brain homogenates manganese (0 to 10 microM) concentration-dependently inhibited propagation of lipid peroxidation caused by iron (0 to 5 microM). Without the contribution of manganese-superoxide dismutase manganese was still effective in sodium azide and/or heat-pretreated brain homogenates. Surprisingly, iron but not manganese, catalysed the Fenton reaction or the conversion of hydrogen peroxide to hydroxyl radicals. The results indicate that iron and manganese are two transition metals mediating opposite effects in the nigrostriatal system, as pro-oxidant and antioxidant, respectively. In conclusion, intranigral infusion of iron, but not manganese, provides an animal model for studying the pathophysiological role of oxidant and oxidative stress in nigrostriatal degeneration and Parkinsonism. The present results further suggest that the atypical antioxidative properties of manganese may protect substantia nigra compacta neurons from iron-induced oxidative stress.
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PMID:Manganese: a transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of parkinsonism. 968 49

We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 37 patients with Parkinson's disease (PD) and 37 matched controls. The CSF levels of zinc were significantly decreased in PD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between PD-patient and control groups. There was no influence of antiparkinsonian therapy on CSF levels of none of these transition metals. These values were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group, with the exception of CSF copper levels with the duration of the disease (r = 0.38, p < 0.05). These results suggest that low CSF zinc concentrations might be related with the risk for PD, although they could be related with oxidative stress processes.
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PMID:Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease. 972 Sep 77

It is an increasingly popular hypothesis that the continued degeneration of dopaminergic neurons in Parkinson's disease (PD) may be the consequence of aberrant oxidation of dopamine and resultant generation of DNA reactive species in PD patients receiving levodopa (l-DOPA) therapy. Occupational metal exposure, particularly to manganese, is a risk factor for Parkinsonism and manganese has been shown to be a true catalyst for dopamine oxidation lending support to this hypothesis. In the present studies, we demonstrate that the antiproliferative activity of l-DOPA and dopamine on Chinese Hamster V79 cells is enhanced by at least an order of magnitude by concomitant exposure to manganese chloride or copper sulfate (500 microM), but not to iron(III) or zinc. Moreover, manganese and copper confer strong clastogenic properties to both compounds as detected in an in vitro micronucleus assay in V79 cells. Metal catalyzed oxidation of drug was associated with the development of a brown-black particulate substance presumed to be a melanin precursor formation. The extent of formation of this precursor paralleled clastogenicity. Metal-enhanced effects were completely antagonized by the concurrent addition of cysteine or reduced glutathione to the cultures. These findings are in support of the hypothesis that aberrant oxidation of dopamine resulting from non-physiological levels of catalytic metals may contribute to the death of dopaminergic neurons and further suggest that oxidation-dependent DNA damage may be the basis for this cell death.
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PMID:Enhancement of cytotoxicity and clastogenicity of l-DOPA and dopamine by manganese and copper. 972 32

Manganese is known to induce neurological disorders similar to parkinsonisms. A dopamine deficiency has been demonstrated in Parkinson's disease and in chronic manganese poisoning, suggesting that the mechanisms underlying the neurotoxic effects of the metal ion are related to a functional abnormality of the extrapyramidal system. However, the details have yet to be elucidated. Here we report that manganese causes characteristic internucleosomal DNA fragmentation, a biochemical hallmark of apoptosis, in PC12 cells. It was transcription dependent, relatively specific for manganese, and blocked in Bcl-2-overexpressed PC12 cells. The results indicate that apoptosis may play a role in the dopaminergic neurotoxicity associated with manganese, the first metal to be reported to induce this form of cell death. The early biochemical events show the impairment of energy metabolism, and the process may require new synthesis of proteins such as c-Fos and c-Jun. In addition, manganese induces phosphorylation of c-Jun at Ser63 and Ser73 and SEK1/MKK4 (c-Jun N-terminal kinase kinase) at Thr258 and tyrosine phosphorylation of several proteins. These results indicate that manganese activates specific signal cascades including the c-Jun N-terminal kinase pathway.
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PMID:Activation of JNK pathway and induction of apoptosis by manganese in PC12 cells. 975 Nov 94

A variety of in vitro and in vivo studies demonstrate that dopamine is a toxic molecule that may contribute to neurodegenerative disorders such as Parkinson's disease and ischemia-induced striatal damage. While much attention has focused on the fact that the metabolism of dopamine produces reactive oxygen species (peroxide, superoxide, and hydroxyl radical), growing evidence suggests that the neurotransmitter itself may play a direct role in the neurodegenerative process. Oxidation of the dopamine molecule produces a reactive quinone moiety that is capable of covalently modifying and damaging cellular macromolecules. This quinone formation occurs spontaneously, can be accelerated by metal ions (manganese or iron), and also arises from selected enzyme-catalyzed reactions. Macromolecular damage, combined with increased oxidant stress, may trigger cellular responses that eventually lead to cell death. Reactive quinones have long been known to represent environmental toxicants and, within the context of dopamine metabolism, may also play a role in pathological processes associated with neurodegeneration. The present discussion will review the oxidative metabolism of dopamine and describe experimental evidence suggesting that dopamine quinone may contribute to the cytotoxic and genotoxic potential of this essential neurotransmitter.
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PMID:Cytotoxic and genotoxic potential of dopamine. 1022 Jan 7

Manganese toxicity has been associated with clinical symptoms of neurotoxicity which are similar to the symptoms observed in Parkinson's disease. Earlier reports indicated that reactive microglia was present in the substantia nigra of patients with Parkinson's disease. Using N9 microglial cells, the current study was designed to determine whether high levels of manganese were associated with microglial activation. Results indicated that manganese significantly increased the bacterial lipopolysaccharide-induced nitric oxide production. This potent activity of manganese was not shared by other transition metals tested, including iron, cobalt, nickel, copper and zinc. Immunohistochemical staining and Western blot analysis indicated that manganese increased the cellular production of inducible nitric oxide synthase. Northern blot analysis indicated that manganese likely increased iNOS gene transcription since this agent increased the mRNA level of the inducible nitric oxide synthase. In contrast to other transition metals tested, manganese did not appear to be cytotoxic to microglial cells. These results suggested that manganese could induce sustained production of neurotoxic nitric oxide by activated microglial cells, which might cause detrimental consequences to surrounding neurons.
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PMID:Manganese potentiates nitric oxide production by microglia. 1032 Jul 80

Manganese intoxication can result in a syndrome of parkinsonism and dystonia. If these extrapyramidal findings are present, they are likely to be irreversible and even progress after termination of the exposure to manganese. Clinical features are usually sufficient to distinguish these patients from those with Parkinson's disease. The neurological syndrome does not respond to levodopa. Imaging of the brain may reveal MRI signal changes in the globus pallidus, striatum, and midbrain. Positron emission tomography reveals normal presynaptic and postsynaptic nigrostriatal dopaminergic function. The primary site of neurological damage has been shown by pathological studies to be the globus pallidus. The mechanism of toxicity is not clear.
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PMID:Manganese neurotoxicity: a review of clinical features, imaging and pathology. 1038 86


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