UMLS:C0030567 - FACTA Search

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present communication surveys the present knowledge about the extent to which formation of free radicals in the central nervous system may give rise to cross-linking reactions finally ending in the deposition of lipofuscin pigments. Free radicals may be formed by autoperoxidation of polyunsaturated fatty acids. These fatty acids, e.g., C22:6 omega 3, are enriched in rods and cones of the eye and in phosphatidyl ethanolamine of synaptosomes. By peroxidation, malondialdehyde is formed. This aldehyde may cross-link through amino groups of proteins and certain phospholipids. Hereby, lipofuscin is deposited. The peroxidation process is counteracted by certain enzymic systems and by antioxidants. Thus, glutathionperoxidase (GSH-Px), catalase and superoxid dismutase may eliminate peroxides. GSH-Px is a selenium-containing enzyme. Peroxides are also formed by metabolic transformation of dopamine. 3 demential syndromes, i.e. Alzheimer's, Parkinson's and Batten's diseases, are discussed with regard to whether the "free radical theory" may explain the pathogenesis. Finally, it is discussed whether an antioxidative treatment including vitamins E and C as well as a supplement of selenium, e.g. sodiumselenite, may be a therapeutic alternative to other types of treatment of demential syndromes or a direct supplement to the L-DOPA treatment of Parkinson's disease.
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PMID:Demential syndromes and the lipid metabolism. 650 44

Mofegiline or MDL 72,974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine hydrochloride) is a selective enzyme-activated irreversible inhibitor of monoamine oxidase B, which is under development for use in the treatment of Parkinson's disease. Male beagle dogs were given single p.o. (20 mg/kg) and i.v. (5 mg/kg) doses of [14C]-Mofegiline. Total radioactivity excreted in urine and feces over 96 hr was, respectively, 75.5 +/- 3.8 and 6.3 +/- 3.4% of the dose after p.o. and 67.9 +/- 0.5 and 3.9 +/- 2.4% after i.v. administration. Unchanged drug in urine represented 3% of the dose after po and less than 1% after i.v. administration. Mofegiline was thus extensively metabolized in dogs, and urinary excretion was the major route of elimination of metabolites. HPLC, with on-line radioactivity detection, showed the presence of four major peaks (M1, M2, M3, and M4), representing respectively 50, 9, 5, and 0.5% of the administered dose excreted in 0-24 hr urine. TSP-LC-MS, FAB-MS, and NMR spectra of the purified metabolites were obtained. M1, the major metabolite in dogs, was shown to have undergone defluorination of the beta-fluoromethylene moiety, and one carbon addition. Its structure was confirmed to be a cyclic carbamate. M2 was a N-carbamoyl O-beta-D-glucuronide conjugate of parent drug. The formation of M1 and M2 is likely to involve initial reversible addition of CO2 to the primary amine function. M3 was a N-succinyl conjugate of the parent drug. M4 had also undergone defluorination to yield a urea adduct of an unsaturated alpha, beta aldehyde. Structures of M1 and M3 were further confirmed by comparing their MS and NMR spectra with those of authentic reference compounds. TSP-LC-MS ion chromatograms of human urine, obtained from two male volunteers after p.o. administration of 24 mg of drug, showed selected molecular ion peaks with the same retention time as the metabolites identified in dogs. In humans, these common metabolites represented a similar percentage of the administered dose to that in dogs. The present study demonstrates that NMR, TSP-LC-MS are complementary analytical techniques, which allow structural identification of unhydrolyzed drug conjugates. The formation of carbamates of amine-containing drugs may be more common than previously reported.
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PMID:Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans. 783 26

An endogenous neurotoxin, N-methyl(R)salsolinol, has been proved to be involved in the pathogenesis of Parkinson's disease. Increased level of N-methyl(R)salsolinol in the cerebrospinal fluid and high activity of its synthesizing (R)salsolinol N-methyltransferase in lymphocytes were confirmed in the majority of parkinsonian patients. Recently this neurotoxin was found to induce apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells. In this study, we tried to elucidate the intracellular mechanism of apoptosis induced by N-methyl(R)salsolinol, and proved activation of caspase 3 after incubation with this toxin by Western blot analysis. Further, a caspase 3 inhibitor, acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartic aldehyde, prevented the nucleosomal DNA fragmentation completely. These results demonstrate that caspase 3 mediates apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, which may cause apoptotic cell death of dopamine neurons in Parkinson's disease.
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PMID:Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, is mediated by activation of caspase 3. 1038 Sep 99

Inclusions containing ubiquitin-protein aggregates appear in neurons of patients with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. The relationship between inclusion production and cell viability is not understood. To address this issue, we investigated the response of an established mouse neuronal cell line and of embryonic rat mesencephalic cultures to inhibition of the ubiquitin/proteasome pathway. Two proteasome inhibitors, a peptidyl aldehyde and an epoxy ketone, which cause accumulation of ubiquitinated proteins, were found to enhance expression of stress-inducible genes, including HSP70i and the polyubiquitin genes UbB and UbC. Under these conditions, mRNA and protein levels of the inducible form of cyclooxygenase (COX-2) were upregulated together with its product, PGE(2), a proinflammatory prostaglandin. Proteasomal inhibition also led to stabilization of COX-2 as ubiquitin conjugates, suggesting that the ubiquitin/proteasome pathway contributes to the regulation of COX-2 protein levels. Treatment with antioxidants known to inhibit NFkappaB and AP-1 transcriptional activation failed to abrogate COX-2 upregulation. Instead, these inhibitors exacerbated the stress response by potentiating HSP70i levels while eliciting a decrease in PGE(2) production. These findings suggest that the accumulation of ubiquitinated proteins resulting from proteasome inhibition in neuronal cells is associated with a proinflammatory response that may be an important contributor to neurodegeneration.
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PMID:Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). 1066 14

3,4-Dihydroxyphenylacetaldehyde (DOPAL) has been reported to be a toxic metabolite formed by the oxidative-deamination of dopamine (DA) catalyzed by monoamine oxidase. This aldehyde is either oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase, an NAD-dependent enzyme or reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase. In the present study we examined whether levels of DOPAL are elevated by inhibition of the mitochondrial respiratory chain. Using inhibitors of mitochondrial complexes I, II, III and IV we found that inhibition of complex I and III increased levels of DOPAL and DOPET. Nerve growth factor-induced differentiation of PC12 cells markedly potentiated DOPAL and DOPET accumulation in response to metabolic stress. DOPAL was toxic to differentiated PC12 as well as to SK-N-SH cell lines. Because complex I dysfunction has been implicated in the pathogenesis of Parkinson's disease, the accumulation of DOPAL may explain the vulnerability of the dopaminergic system to complex I inhibition. The rapid appearance of DOPAL and DOPET after inhibition of complex I may be a useful early index of oxidative stress in DA-forming neurons.
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PMID:Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde. 1079 58

Recent works suggest that alpha-synuclein could play a central role in Parkinson's disease (PD). Thus, two mutations were reported to be associated with rare autosomal dominant forms of the disease. We examined whether alpha-synuclein could modulate the caspase-mediated response and vulnerability of murine neurons in response to various apoptotic stimuli. We established TSM1 neuronal cell lines overexpressing wild-type (wt) alpha-synuclein or the PD-related Ala-53 --> Thr mutant alpha-synuclein. Under basal conditions, acetyl-Asp-Glu-Val-Asp-aldehyde-sensitive caspase activity appears significantly lower in wt alpha-synuclein-expressing cells than in neurons expressing the mutant. Interestingly, wt alpha-synuclein drastically reduces the caspase activation of TSM1 neurons upon three distinct apoptotic stimuli including staurosporine, etoposide, and ceramide C(2) when compared with mock-transfected cells. This inhibitory control of the caspase response triggered by apoptotic agents was abolished by the PD-related pathogenic mutation. Comparison of wild-type and mutated alpha-synuclein-expressing cells also indicates that the former exhibits much less vulnerability in response to staurosporine and etoposide as measured by the sodium 3'-[1-(phenylaminocarbonyl)-3, 4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid assay. Altogether, our study indicates that wild-type alpha-synuclein exerts an antiapoptotic effect in neurons that appears to be abolished by the Parkinson's disease-related mutation, thereby suggesting a possible mechanism underlying both sporadic and familial forms of this neurodegenerative disease.
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PMID:Wild-type but not Parkinson's disease-related ala-53 --> Thr mutant alpha -synuclein protects neuronal cells from apoptotic stimuli. 1081 98

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a toxic metabolite formed by the oxidative deamination of dopamine. This aldehyde is mainly oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH), but is also partly reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase (ARs). In a previous study, we found that rotenone, a complex I inhibitor, induced a rapid accumulation of DOPAL and DOPET in the medium of cultured PC12 cells. Here, we examined the potential role of DOPAL in the toxicity induced by complex I inhibition in PC12 cells and compared the effects of rotenone on concentrations of DOPAL and DOPET to those of MPP(+). DOPAL and DOPET levels were increased by rotenone but decreased by MPP(+). Inhibition of ALDH by daidzein reduced the formation of DOPAC and increased the accumulation of DOPAL. Inhibition of ARs (with AL1576) diminished DOPET formation and elevated DOPAL concentrations. Combined inhibition of ALDH and ARs markedly elevated DOPAL concentrations while diminishing DOPET and DOPAC levels. The elevation of DOPAL levels induced by combined inhibition of ALDH and ARs had no effect on cell viability. However, combined inhibition of ALDH and ARs potentiated rotenone-induced toxicity. Both the potentiation of toxicity and the increase in DOPAL levels were blocked by inhibition of monoamine oxidase with clorgyline indicating that accumulation of DOPAL was responsible for the potentiated rotenone-induced toxicity following combined inhibition of ALDH and ARs. Since complex I dysfunction is reported to be involved in the pathogenesis of Parkinson's disease, DOPAL potentiation of the deleterious effects of complex I inhibition may contribute to the specific vulnerability of dopaminergic neurons to injury.
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PMID:3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells. 1085 71

Mutations in alcohol dehydrogenase (ADH; EC 1.1.1.1) genes may be of interest in the etiology of Parkinson's disease (PD) because of the important role these enzymes play in retinoid and dopamine metabolism and/or aldehyde detoxification. The location of several alcohol dehydrogenase genes in a cluster on chromosome 4 lends further support to ADH genes being candidates for this disorder, because recently a form of autosomal-dominant parkinsonism has been mapped to this area. We sequenced the promoter and coding regions and part of the introns of the human class IV ADH gene in 10 patients with PD. Seven different polymorphisms were identified. These polymorphisms could be assigned to four alleles (A1-A4). We then determined the frequencies of those four alleles and the wild-type allele in 78 patients with PD and 130 control subjects and found a significant association of the A1 allele with PD (odds ratio = 2.87; 95% confidence interval = 1.35-6.08). In familial cases, the association was strongest (odds ratio = 4.86; 95% confidence interval = 1.89-12.75). Two patients were homozygous for A1 whereas none of the 130 control subjects was found to be homozygous. Our results show an association between a certain ADH4 (formerly known as ADH7 in humans) allele and PD. This suggests a role for genetic variations of ADH4 as risk factors for the development of PD. Our data also show that the observed polymorphisms alone are not sufficient to cause symptoms. Further genetic and/or environmental factors have to be involved.
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PMID:Alcohol dehydrogenase alleles in Parkinson's disease. 1100 84

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

Parkinson's disease occurs in 1% of people over the age of 65 when about 60% of the dopaminergic neurons in the substantia nigra of the midbrain are lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed in dopaminergic neurons by redox cycling of MPP+, the active metabolite of MPTP. This redox cycling mechanism involves the reduction of MPP+ by a number of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neurons and is responsible for the synthesis of dopamine. However, tyrosine hydroxylase can form oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to form oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may be oxidized by aldehyde dehydrogenase with the formation of oxygen radicals and 3,4-dihydroxyphenylacetic acid. The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented.
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PMID:Parkinson's disease--redox mechanisms. 1137 51

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