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)

Free radical are highly reactive chemical species with an unpaired electron in an atomic or molecular orbital. In biological systems, the most important free radicals are superoxide anion and hydrogen peroxide; in the presence of transition metals such as iron, copper and manganese both these free radicals produce hydroxyl radicals. Free radicals attack proteins, nuclei acids and membranes containing large quantities of polyunsaturated fatty acids. Because of their toxicity, the organism has developed ways to deactivate them. The superoxide dismutase enzyme (SOD) catalyzes dismutation of the superoxide radical into hydrogen peroxide and oxygen hydrogen peroxide is in turn reduced to water and oxygen by peroxidase glutathione and catalase enzymes. The production of radicals in the brain is due to catecholamine metabolism such as dopamine and norepinephrine and is increased by the presence of transition metals and by a deficiency of antioxidant agents such as vitamin E. Two main groups of dementia exist in older age: the multi-infarctual dementias, caused by cerebrovascular disorders and the primary degenerative disorders such as Alzheimer, where no vascular disease is evident. Free radicals play an important role in Parkinson's disease, in Alzheimer's disease and in stroke. The value of SOD and CAT activity following the above mentioned degenerative diseases differ among the various studies carried out. In Alzheimer's disease, the value of SOD activity probably increases in the neuropathologically involved areas. In stroke, the SOD value does not vary either in the ischemic area or in the peri-infarctual one during the first 24 hrs after lesion, while the CAT value decreases.
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PMID:Free radicals: important cause of pathologies refer to ageing. 1070 16

Intracellular proteinaceous aggregates are hallmarks of many common neurodegenerative disorders, and recent studies have shown that alpha-synuclein is a major component of several pathological intracellular inclusions, including Lewy bodies in Parkinson's disease (PD) and glial cell inclusions in multiple system atrophy. However, the molecular mechanisms underlying alpha-synuclein aggregation into filamentous inclusions remain unknown. Since oxidative and nitrative stresses are potential pathogenic mediators of PD and other neurodegenerative diseases, we asked if oxidative and/or nitrative events alter alpha-synuclein and induce it to aggregate. Here we show that exposure of human recombinant alpha-synuclein to nitrating agents (peroxynitrite/CO(2) or myeloperoxidase/H(2)O(2)/nitrite) induces formation of nitrated alpha-synuclein oligomers that are highly stabilized due to covalent cross-linking via the oxidation of tyrosine to form o,o'-dityrosine. We also demonstrate that oxidation and nitration of pre-assembled alpha-synuclein filaments stabilize these filaments to withstand denaturing conditions and enhance formation of SDS-insoluble, heat-stable high molecular mass aggregates. Thus, these data suggest that oxidative and nitrative stresses are involved in mechanisms underlying the pathogenesis of Lewy bodies and glial cell inclusions in PD and multiple system atrophy, respectively, as well as alpha-synuclein pathologies in other synucleinopathies.
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PMID:Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. 1074 81

Experimental and clinical studies of neural transplantation in Parkinson's disease have focused on the placement of fetal dopaminergic grafts not in their ontogenic site (substantia nigra) but in the main nigral target area (striatum). The reason for this is the apparent inability of intranigral nigral grafts to extend axons for long distances reinnervating the ipsilateral striatum. This review presents previous work by our laboratory [I. Mendez, M. Hong, Reconstruction of the striato-nigro-striatal circuitry by simultaneous double dopaminergic grafts: a tracer study using fluorogold and horseradish peroxidase, Brain Res. 778 (1997) 194-205; I. Mendez, D. Sadi, M. Hong., Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants, J. Neurosci. 16 (1996) 7216-7227] using a new transplantation strategy aimed at restoring dopaminergic innervation of the nigra and striatum by simultaneous dopaminergic transplants placed in the substantia nigra and ipsilateral striatum (double grafts) in the 6-hydroxydopamine lesioned adult rat brain. These double grafts achieve not only greater striatal reinnervation than the standard intrastriatal grafts but also produce a faster and more complete behavioural recovery six weeks after transplantation. Injection of the retrograde tracer fluorogold into the striatum and nigra resulted in fluorescent labeled cells within the intranigral graft and the intrastriatal graft and surrounding striatum, respectively suggesting that these double grafts promote at least partial reconstruction of the nigrostriatal dopaminergic pathway. This double graft strategy may have potential implications in clinical neural transplantation for Parkinson's disease.
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PMID:Simultaneous intrastriatal and intranigral grafting (double grafts) in the rat model of Parkinson's disease. 1075 81

Using a combination of metabolic measurement and retrograde tracing, we show that the neurons in the pedunculopontine nucleus and parafascicular nucleus of the thalamus that project to the subthalamic nucleus are hyperactive after nigrostriatal dopaminergic denervation in rats. In Parkinson's disease, the loss of dopaminergic neurons induces a cascade of functional changes in the basal ganglia circuitry including a hyperactivity of the subthalamic nucleus. This hyperactivity is thought to be due to a diminution of the inhibitory pallidal influence. However, recent studies have suggested that other cerebral structures are involved in the subthalamic neuronal hyperactivity. This study was undertaken to identify these cerebral structures. Neurons projecting to the subthalamic nucleus were identified by retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase, injected into the subthalamic nucleus of rats with 6-hydroxydopamine unilateral lesion of the substantia nigra pars compacta and sham-lesioned animals. Metabolic activity was determined in the same neurons using in situ hybridization for the first subunit of cytochrome oxidase messenger RNA, a metabolic marker, and image analysis. Horseradish peroxidase-labeled neurons were found in the globus pallidus, parafascicular and pedunculopontine nucleus and sometimes in raphe nuclei and the substantia nigra pars compacta. Measurement of metabolic activity was performed for the globus pallidus, the pedunculopontine and parafascicular nuclei. The expression level of the first subunit of cytochrome oxidase messenger RNA in neurons projecting to the subthalamic nucleus was 62% higher in parafascicular neurons and 123% higher in pedunculopontine neurons in 6-hydroxydopamine-lesioned rats, compared to sham-lesioned animals. An increase was also observed in the globus pallidus, but did not reach significance. Our results suggest that hyperactivity of subthalamic neurons could be due, at least in part, to an increase of excitatory input arising from the pedunculopontine and parafascicular nuclei. These data also suggest that the latter structures may play an important role in the physiopathology of Parkinson's disease.
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PMID:Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson's disease. 1077 41

The underlying cause of the selective death of the nigral dopaminergic neurons in Parkinson's disease is not fully understood. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of dopamine and nitric oxide. Because BH4 contributes to the syntheses of these two potential oxidative stressors and also undergoes autoxidation, thereby producing reactive oxygen species, it was possible that BH4 may play a role in the selective vulnerability of dopaminergic cells. BH4 given extracellularly was cytotoxic to catecholamine cells CATH. a, SK-N-BE(2)C, and PC12, but not to noncatecholamine cells RBL-2H3, CCL-64, UMR-106-01, or TGW-nu-1. This was not caused by increased dopamine or nitric oxide, because inhibition of their syntheses did not attenuate the damage and BH4 did not raise their cellular levels. Dihydrobiopterin and biopterin were not toxic, indicating that the fully reduced form is responsible. The toxicity was caused by generation of reactive oxygen species, because catalase, superoxide dismutase, and peroxidase protected the cells from the BH4-induced demise. Furthermore, thiol agents, such as reduced glutathione, dithiothreitol, beta-mercaptoethanol, and N-acetylcysteine were highly protective. The BH4 toxicity was initiated extracellularly, because elevation of intracellular BH4 by sepiapterin did not result in cell damage. BH4 was spontaneously released from the cells of its synthesis to a large extent, and the release was not further enhanced by calcium influx. This BH4-induced cytotoxicity may represent a mechanism by which selective degeneration of dopaminergic terminals and neurons occur.
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PMID:Tetrahydrobiopterin is released from and causes preferential death of catecholaminergic cells by oxidative stress. 1095 58

The main metabolic pathway affected in Parkinson's disease is that of dopamine oxidation and melanin formation in substantia nigra which involves both oxidative and reductive enzymes. The cyclic nature of the biosynthetic pathway from dopamine to melanin implies that a derangement at any of the steps may result in the disappearance of melanin. Possible pathogenetic events such as oxidative stress have therefore no clearcut interpretation since they may be both cause or consequence of the disease. This paper documents the existence of a peroxidase converting dopamine to dopaminochrome in the presence of hydrogen peroxide in the substantia nigra of autopsied human brain. The activatory effect of dopaminochrome on a purified peroxidase is shown, together with the inhibitory effect of dopaminochrome-derived melanin and the activatory effect of melanin/Fe. The toxic effect of dopaminochrome on murine neuroblastoma cells cultured in vitro is demonstrated together with the inhibition of dopaminochrome melanization induced by acetylcholine in vitro.
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PMID:Enzymatic dopamine peroxidation in substantia nigra of human brain. 1095 69

Reactive oxygen species produce a wide spectrum of DNA damage, including oxidative base damage and abasic (AP) sites. Many procedures are available for the quantification and detection of base damage and AP sites. However, either these procedures are laborious or the starting materials are difficult to obtain. A biotinylated aldehyde-specific reagent, ARP, has been shown to react specifically with the aldehyde group present in AP sites, resulting in biotin-tagged AP sites in DNA. The biotin-tagged AP sites can then be determined colorimetrically with an ELISA-like assay, using avidin/biotin-conjugated horseradish peroxidase as the indicator enzyme. The ARP assay is thus a simple, rapid, and sensitive method for the detection of AP sites in DNA. Furthermore, removal of damaged base by DNA N-glycosylases generates AP sites that can be measured by the ARP reagent. By coupling the ARP assay with either endonuclease III from Escherichia coli or 8-oxoguanine N-glycosylase (OGG1) from yeast, investigators can rapidly determine the amount of oxidative pyrimidine damage (endonuclease III-sensitive sites) or purine damage (OGG1-sensitive sites) in cellular DNA, respectively. An increased level of oxidative damage has been implicated in several age-related human diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease, as well as the aging process. The sensitivity and simplicity of the ARP assay thus make it a valuable method for investigators who are interested in estimating the level of oxidative DNA damage in cells and tissues derived from patients with various age-related diseases or cancers.
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PMID:Detection of abasic sites and oxidative DNA base damage using an ELISA-like assay. 1102 Mar 31

There is strong evidence that oxidative stress participates in the etiology of Parkinson's disease (PD). We designed this study to investigate the neuroprotective effect of vitamin E in the early model of PD. For this purpose, unilateral intrastriatal 6-hydroxydopamine (12.5 microg/5 microl) lesioned rats were pretreated intramuscularly with D-alpha-tocopheryl acid succinate (24 I.U./kg, i.m.) 1 h before and three times per week for 1 month post-surgery. Apomorphine- and amphetamine-induced rotational behavior was measured postlesion fortnightly. A parallel tyrosine hydroxylase immunoreactivity and wheat germ agglutinin-horse radish peroxidase (WGA-HRP) tract-tracing study was performed to evaluate the vitamin E pretreatment efficacy. Tyrosine hydroxylase-immunohistochemical analyses showed a reduction of 18% in ipsilateral substantia nigra pars compacta (SNC) cell number of the vitamin E-pretreated lesioned (L+E) group comparing with contralateral side. The cell number dropped to 53% in the lesioned (L+V) group. In addition, retrograde-labeled neurons in ipsilateral SNC were reduced by up to 30% in the L+E group and 65% in the L+V group. Behavioral tests revealed that there are 74% and 68% reductions in contraversive and ipsiversive rotations in the L+E group, respectively, as compared with the L+V group. Therefore repeated intramuscular administration of vitamin E exerts a rapid protective effect on the nigrostriatal dopaminergic neurons in the early unilateral model of PD.
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PMID:Neuroprotective effect of vitamin E on the early model of Parkinson's disease in rat: behavioral and histochemical evidence. 1117 67

Apoptosis is a form of cell death that is manifested in Parkinson's disease (PD) and certain other neurodegenerative disorders. Metabolites of salsolinol (SAL), an intraneuronal, dopamine-derived tetrahydroisoquinoline (TIQ), have been shown to induce apoptosis in human dopaminergic neuroblastoma cells, implicating these molecules as causative or contributory factors in the selective killing of nigrostriatal dopaminergic neurons, a cardinal manifestation of Parkinson's disease. Since insects employ dopamine and related catecholamines in a variety of processes including cuticular sclerotization and cellular immune reactions, it was of interest to know how insect cells metabolized exogenous SAL. Propidium iodide staining combined with flow cytometry showed that IPLB-LdFB cells from Lymantria dispar exhibited no significant (P < 0.05) increase in apoptosis when incubated for 48 h with concentrations of SAL ranging from 10 microM to 1 mM. A significant increase in apoptosis (P < 0.05) was observed in cell cultures containing the highest concentration of SAL tested (5 mM), but only 12.4% of the cells manifested this form of cell death. High pressure liquid chromatography with electrochemical detection (HPLC-ED) was used to document the production of two potentially cytotoxic quinonoids generated during the autoxidation of SAL, a reaction that was found to be significantly (P < 0.05) enhanced by peroxidase. The resistance of IPLB-LdFB cells to SAL-induced apoptosis is attributed to the ability of these insect cells to metabolize and/or detoxify such dopamine-derived catecholic TIQs. Thus, the biochemical pathways employed by insect cells in these processes may be of considerable interest to individuals investigating certain neurodegenerative disorders.
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PMID:Resistance of the insect cell line IPLB-LdFB to salsolinol-induced apoptosis. 1175 89

Catechol estrogens and catecholamines are metabolized to quinones, and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogenic benzene can also be oxidized to its quinone. We report here that quinones obtained by enzymatic oxidation of catechol and dopamine with horseradish peroxidase, tyrosinase or phenobarbital-induced rat liver microsomes react with DNA by 1,4-Michael addition to form predominantly depurinating adducts at the N-7 of guanine and the N-3 of adenine. These adducts are analogous to the ones formed with DNA by enzymatically oxidized 4-catechol estrogens (Cavalieri,E.L., et al. (1997) PROC: Natl Acad. Sci., 94, 10937). The adducts were identified by comparison with standard adducts synthesized by reaction of catechol quinone or dopamine quinone with deoxyguanosine or adenine. We hypothesize that mutations induced by apurinic sites, generated by the depurinating adducts, may initiate cancer by benzene and estrogens, and some neurodegenerative diseases (e.g. Parkinson's disease) by dopamine. These data suggest that there is a unifying molecular mechanism, namely, formation of specific depurinating DNA adducts at the N-7 of guanine and N-3 of adenine, that could initiate many cancers and neurodegenerative diseases.
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PMID:Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases. 1208 31


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