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)

Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2-nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components.
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PMID:Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. 868 11

Parkinson's disease is characterized by dopaminergic neuronal degeneration, but its pathogenic mechanism is still unknown. In the dopaminergic neurons, oxygen radicals such as hydrogen peroxide are released through dopamine oxidation. Many factors are involved in radical formation, but glutamate and nitric oxide (NO) are the major effectors of the radical-induced neurotoxicity mediated primarily through calcium influx. In the cultured embryonic rat mesencephalon, we investigated the dopaminergic and non-dopaminergic neuronal death induced by glutamate and by NO-generating agents. Although glutamate had a neurotoxic effect on both dopaminergic and non-dopaminergic neurons, it showed slightly greater effect in the dopaminergic neurons. In contrast to glutamate, NO-generating agents (S-nitrosocysteine and sodium nitroprusside) showed neurotoxic effects restricted exclusively to non-dopaminergic neurons. Although N omega-nitro-L-arginine, and NO synthase inhibitor, had no significant effect on the glutamate-induced cytotoxicity in dopaminergic neurons, it had a significant antagonistic effect on that in non-dopaminergic neurons. These findings indicate the presence of two different mechanisms of glutamate-induced neuronal death, one being neurotoxicity not mediated by NO, found in dopaminergic neurons, and the other being that mediated via NO, found in non-dopaminergic neurons.
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PMID:Different mechanisms of glutamate-induced neuronal death between dopaminergic and non-dopaminergic neurons in rat mesencephalic culture. 869 37

We studied nitrogen radical nitric oxide (.NO) release and reactive oxygen species (ROS) production by isolated neutrophils after phorbol myristate acetate (PMA) stimulation in 12 newly diagnosed and nine treated Parkinson's disease (PD) patients and 10 age-matched healthy controls. Neutrophils of both groups of PD patients had an elevated PMA-activated release of .NO [61 and 57%, respectively, higher than that of controls (p < 0.05)]. In contrast, H2O2 release was only significantly increased by 56% in chronically treated patients. In agreement, the maximum rate of luminol-dependent chemiluminescence, which partly represents O2- H2O2- .NO interactions, was increased only in the treated group. When other blood markers of oxidative stress were compared, only erythrocyte catalase activity was decreased in both PD patient series by 33 and 39%, respectively (p < 0.05), whereas plasma antioxidant capacity and erythrocyte superoxide dismutase activity levels were decreased only in treated PD patients. This study suggests that neutrophils express a primary alteration of .NO release in PD patients, whereas H2O2 and oxidative-stress parameters are more probably related to the evolution of PD or to effects of treatment with L-dopa.
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PMID:Neutrophil function, nitric oxide, and blood oxidative stress in Parkinson's disease. 872 42

Oxidative stress refers to the cytopathologic consequences of a mismatch between the production of free radicals and the ability of the cell to defend against them. Growing data from experimental models and human brain studies suggest oxidative stress may play an important role in neuronal degeneration in diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Mitochondrial oxidative metabolism, nitric oxide, phospholipid metabolism, and proteolytic pathways are potential sources of intracellular free radicals. Alterations in free radical defense systems may also contribute to oxidative stress. A net increase in reactive oxygen species can produce damage to lipids, proteins, and DNA and induce necrosis or apoptosis. Elucidating the pathways important in the production of and defense from free radicals may be important in devising new pharmacologic strategies to slow or halt neuronal degeneration.
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PMID:Oxidative stress in neurodegenerative diseases. 872 83

We review the recent progress in the research of the etiology, pathogenesis and treatment of Parkinson's disease. It has been postulated that mitochondrial respiratory failure and oxidative stress are two major contributors to nigral cell death in Parkinson's disease. Loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the substantia nigra has been reported. Evidence to indicate oxidative stress includes a high dopamine content, increase in superoxide dismutase activities, increase in iron, and decrease in glutathione in the substantia nigra. The question posed is which one occurs first. We believe mitochondrial respiratory failure occurs first, because slowing down of the electron transport induces an increase in the formation of activated oxygen species. The primary cause of Parkinson's disease is still unknown, but we believe the interaction of environmental toxins and genetic predispositions is important. In this respect, molecular genetic studies on familial Parkinson's disease are very important.
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PMID:Parkinson's disease: from etiology to treatment. 877 62

The reactions of dopamine (1-amino-2-(3,4-dihydroxyphenyl)-ethane, DA), 5-hydroxydopamine (5-OHDA), and 6-hydroxydopamine (6-OHDA), with molecular oxygen-with and without the addition of catalytic amounts of iron(III) and other metal ions-have been studied and the implication of these results with respect to the chemistry involved in the progress of Parkinson's disease is discussed. In the presence of O2 DA reacts spontaneously without the necessity of metal-ion catalysis under the production of stoichiometric amounts of H2O2, to form initially pink dopaminochrome, which is not stable and reacts further (without the consumption of dioxygen) to form the insoluble polymeric material known as 'melanine'. DA reacts with iron(III) yielding an intermediate 1:1 complex, which decomposes releasing Fe(II) and the semiquinone, which reacts further under involvement of both Fe(III) and dioxygen. 6-OHDA reacts without showing the necessity of such an intermediate, and it is shown to be able to release iron as Fe(II) from ferritine. On the other hand, it is shown (in vitro) that Fe(II) reacts in a Fenton type reaction with DA and the present H2O2 producing 5-OHDA and especially 6-OHDA. Based on these mutual interacting reactions a mechanism for the initiation and progress of Parkinson's disease is suggested. The catalytic effects of some other transition-metal ions are presented and an explanation for the peculiarly toxic effects of manganese(II) is put forward. Finally, a possible reason for the effect that nicotine has in the mitigation of Parkinson's disease is discussed.
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PMID:Dopamine, 6-hydroxydopamine, iron, and dioxygen--their mutual interactions and possible implication in the development of Parkinson's disease. 878 34

We have recently shown that dopamine (DA) can trigger apoptosis, an active program of cellular self-destruction, in various neuronal cultures and proposed that inappropriate activation of apoptosis by DA and or its oxidation products may initiate nigral cell loss in Parkinson's disease (PD). Since DA toxicity may be mediated via generation of oxygen-free radical species, we examined whether DA-induced cell death in PC12 cells may be inhibited by antioxidants. We have found that the thiol containing compounds, reduced glutathione (GSH), N-acetyl-cysteine (NAC), and dithiothreitol (DTT) were markedly protective, while vitamins C and E had lesser or no effect. The thiol antioxidants and vitamin C but not vitamin E, prevented dopamine autooxidation and production of dopamine-melanin. Their protective effect has also manifested by inhibiting DA-induced apoptosis; DNA fragmentation was prevented as was shown histochemically by the in situ end-labeled DNA technique (TUNEL). Intracellular GSH and other thiols constitute an important natural defense against oxidative stress. We have found that depletion of cellular GSH by the addition of phoron, a substrate of glutathione transferase, and buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl transpeptidase, significantly enhanced DA toxicity. Cotreatment with NAC rescued the cells from the toxic effect of BSO+DA, and phoron+ DA, while addition of GSH provided only partial protection from BSO+DA toxicity. Our data indicate that the thiol family of antioxidants, but not vitamins C and E, are highly effective in rescuing cells from DA-induced apoptosis. Further study of the mechanisms underlying the unique protective capacity of thiol antioxidants may lead to the development of new neuroprotective therapeutic strategies for PD.
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PMID:Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson's disease. 879 65

Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss of dopaminergic neurons in the nigrostriatal region of the brain that occurs during normal aging and in Parkinson's disease. In the present study, the potential protective effects of catecholamine O-methylation and of melatonin against catecholamine autoxidation-induced protein damage were assessed in vitro using the oxygen radical absorbance capacity (ORAC) assay. The rate of oxidation of the fluorescent protein porphyridium cruentum beta-phycoerythrin (beta-PE) caused by the oxidizing agent CuSO4 was shown to be accelerated by addition of the catecholamines dopamine and L-dopa. Replacement of dopamine and L-dopa in the assay with their O-methylated metabolites 3-O-methyldopamine and 3-O-methyldopa significantly decreased the rate of beta-PE oxidation. When melatonin was added to the ORAC assay in combination with dopamine or L-dopa, the rate of beta-PE oxidation was decreased as well. These findings were consistent with the following interpretations: (1) O-methylated catecholamines are less susceptible to autoxidation than their nonmethylated precursors, and (2) melatonin, which has recently been shown to be a powerful antioxidant, is capable of scavenging free radicals produced during catecholamine autoxidation. These findings suggest that O-methylation and melatonin may be important components of the brain's antioxidant defenses against catecholamine autoxidation and may protect against consequent dopaminergic neurodegeneration.
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PMID:Oxidative damage caused by free radicals produced during catecholamine autoxidation: protective effects of O-methylation and melatonin. 881 40

Reactive oxygen species are believed to play a crucial role in situations where dopamine neurons die, such as in Parkinson's disease or during intracerebral transplantation of embryonic mesencephalic tissue. The present study was designed to address the question whether, and to what extent, the glutathione redox system is important for the viability of rat embryonic dopamine neurons in vitro. Furthermore, we studied whether the lazaroid U-83836E, a 2-methylaminochroman that inhibits lipid peroxidation, affects the survival of cultured mesencephalic neurons subjected to experimentally induced glutathione depletion. Glutathione depletion was achieved by exposing dissociated mesencephalic cell cultures to L-buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, at four different concentrations (1, 10,100, and 1,000 microM). Dopamine neuron survival was significantly reduced by 65-94% in a concentration-dependent manner by 10-1,000 microM BSO. The neurotoxic effects of BSO were almost completely prevented by supplementing the culture medium with 0.3 microM U-83836E. As assessed by HPLC analysis, BSO treatment was associated with a marked reduction of cellular glutathione content, and this depletion was not altered by the presence of U-83836E. We conclude that in the present insult model of severe glutathione depletion, the lazaroid can afford efficient neuroprotection that does not seem to be mediated by a direct interaction with BSO or glutathione, but rather via an independent pathway.
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PMID:Lazaroid treatment prevents death of cultured rat embryonic mesencephalic neurons following glutathione depletion. 885 50

The mitochondrial electron transport enzyme NADH:ubiquinone oxidoreductase (complex I), which is encoded by both mitochondrial DNA and nuclear DNA, is defective in multiple tissues in persons with Parkinson's disease (PD). The origin of this lesion and its role in the neurodegeneration of PD are unknown. To address these questions, we created an in vitro system in which the potential contributions of environmental toxins, complex I nuclear DNA mutations, and mitochondrial DNA mutations could be systematically analyzed. A clonal line of human neuroblastoma cells containing no mitochondrial DNA was repopulated with mitochondria derived from the platelets of PD or control subjects. After 5 to 6 weeks in culture, these cytoplasmic hybrid (cybrid) cell lines were assayed for electron transport chain activities, production of reactive oxygen species, and sensitivity to induction of apoptotic cell death by 1-methyl-4-phenyl pyridinium (MPP+). In PD cybrids we found a stable 20% decrement in complex I activity, increased oxygen radical production, and increased susceptibility to 1-methyl-4-phenyl pyridinium-induced programmed cell death. The complex I defect in PD appears to be genetic, arising from mitochondrial DNA, and may play an important role in the neurodegeneration of PD by fostering reactive oxygen species production and conferring increased neuronal susceptibility to mitochondrial toxins.
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PMID:Origin and functional consequences of the complex I defect in Parkinson's disease. 887 87


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