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)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), the active product of MPTP, caused Parkinson's disease-like symptoms. The mechanism of action of MPP+ is unknown, but analogues of MPTP lacking an N-methyl group were found to be essentially devoid of toxicity, which means that the methyl group of the pyridine ring plays a role in the toxicity. This is of interest because S-adenosylmethionine (SAM), which is the biologic methyl donor and requires a methyl group for its action, also caused MPP(+)-like motor deficits in rodents. Therefore, the requirement of a methyl group by MPTP and MPP+ for their actions suggests that, like SAM, MPP+ and MPTP may serve as methyl donors. This hypothesis was tested by reacting SAM, MPP+, or MPTP with dopamine in the presence of catechol-O-methyltransferase and measuring the methylated product of dopamine produced. Like SAM, MPP+, but not MPTP, methylated dopamine. The methylated product coeluted from chromatographic columns with standard 3-methoxytyramine. Concentrations of 15.6, 62.5, 250, and 1000 nmoles/tube increased the 3-methoxytyramine recovered above controls by 0.0, 6.88, 44.55, 129.47 and 5.8, 13.9, 50.58, 121.31 nmoles for SAM and MPP+, respectively. The dopamine that remained unreacted was dose-dependently decreased. MPTP had no significant effect. The ability of MPP+ to serve as a methyl donor may represent a mechanism for the toxicity of MPP+.
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PMID:1-Methyl-4-phenylpyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) serves as methyl donor for dopamine: a possible mechanism of action. 159 Sep 12

N-Methyl-4-phenylpyridinium ion (MPP+), a highly toxic metabolite produced in the brain from a street drug contaminant, is selectively taken up by nigrostriatal dopaminergic neurons and accumulated intraneuronally in mitochondria. There it inhibits respiration, causes neuronal death and, in primates, provokes a parkinsonian condition. It has been suggested that endogenously generated or activated agents resembling MPP+ may contribute to the development of Parkinson's disease. We report here that simple beta-carbolines derived from tryptophan or related open chain indoles, when specifically methyl-substituted on both (2[beta] and 9[indole]) available nitrogens, display mitochondrial inhibitory potencies and neurotoxic effects in vitro (PC12 cultures) and in vivo (striatal microdialysis) which approach or even surpass MPP+. These results take on physiological significance with our finding that brain enzyme activity catalyzes S-adenosylmethionine-dependent methylations of the beta- and indole-nitrogens in beta-carbolines that have been detected in vivo. The unusual 9[indole]-N-methyl transfer, previously unrecognized in animals, apparently requires prior methylation of the 2[beta]-nitrogen. Sequential di-N-methylation of endogenous or xenobiotic beta-carbolines to form unique, neurotoxic 2,9-N,N'-dimethyl-beta-carbolinium ions may serve as a brain bioactivation route in chronic neurodegenerative conditions such as Parkinson's disease.
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PMID:Indole-N-methylated beta-carbolinium ions as potential brain-bioactivated neurotoxins. 161 7

Guinea pig brain S-adenosylmethionine (SAM)-dependent N-methyltransferase activity toward physiologically relevant beta-carboline (BC) substrates was examined with reverse-phase HPLC and radiochemical detection. Representative BCs, norharman and harmine, were enzymatically methylated on the 2[beta]-nitrogen by [3H]CH3-SAM in undialyzed homogenates to yield 2[beta]-methylated BCs and subsequently on the 9[indole]-nitrogen to generate 2,9-dimethylated BC products. This may be the first account of mammalian indole N-methyl transfer. There was no HPLC evidence for 9-methyl BC or (from carbon methylation) 2,6-dimethyl BC products. Capillary gas chromatography-mass spectrometry analysis confirmed the structures of the 2,9-dimethyl and 2-methyl products of norharman. The 2[beta]- and 9[indole]-N-methylation activities were mainly in the nuclear fractions and were negligible in undialyzed cytosol. This differs from the cytosolic SAM-dependent N-methylations reported with other azaheterocyclics, including 1,2,3,4-tetrahydro-BCs. The involvement of a single enzyme was suggested because the two N-methyl transfers with BC substrate had similar subcellular activity patterns, regional brain distributions, and Km and Vmax values. Sequential N-methylation of various BCs that have been observed in vivo may be a unique route to centrally retained N2,N9-dimethylated beta-carbolinium ions. Because they resemble the synthetic parkinsonian toxicant, N-methyl-4-phenylpyridinium, with respect to structure and neurotoxic activity, such "bioactivated" carbolinium ions could be endogenous causative factors in Parkinson's disease.
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PMID:Novel S-adenosylmethionine-dependent indole-N-methylation of beta-carbolines in brain particulate fractions. 162 24

This paper reviews and correlates three separate recent findings that implicate the one-carbon cycle in neuropsychiatric disease: (i) the demonstration by kinetic studies that the Vmax of methionine adenosine transferase (MAT) is reduced in some schizophrenics and depressives and is increased in some manics, and that the activity of serine hydroxymethyltransferase (SHMT) is reduced in a further subpopulation of schizophrenics; (ii) the demonstration that S-adenosylmethionine (the product of MAT) is an effective clinical antidepressant; and (iii) the reports that L-methionine is an effective treatment for certain of the symptoms of Parkinson's disease. These clinical findings may be correlated with recent findings that transmethylation reactions (lipid and carboxymethylation) play an important role in synaptic events (coupling of receptors to adenylate cyclase and release of neurotransmitters).
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PMID:The role of the one-carbon cycle in neuropsychiatric disease. 632 30

S-Adenosyl-L-methionine has been shown to cause Parkinson's disease-like effects that include hypokinesia, tremor, rigidity, and abnormal posture. S-Adenosyl-L-methionine is the rate-limiting endogenous methyl donor. Its biochemical role, which includes the metabolism of dopamine and the synthesis of acetylcholine, also resembles the changes that occur in Parkinson's disease. Therefore, S-adenosyl-L-methionine may play a role in Parkinson's disease-like motor impairments. In this study we manipulated the levels of S-adenosyl-L-methionine in the brain of rats and quantified the changes in hypokinetic type motor activity that seems to occur also in Parkinsonism. Male Sprague-Dawley rats were anesthetized with chloral hydrate (400 mg/kg/rat), cannulated, injected into the lateral ventricle with S-adenosyl-L-methionine or saline, and their motor activity was measured in a Digiscan Animal Activity Monitor. Other behaviors were also observed. S-Adenosyl-L-methionine caused hypokinesia, tremor, rigidity, and abnormal posture in rats. Motor activity was significantly decreased within 2 min postinjection. The hypokinesia was maximal at 60 min, at which time a 65, 75, and 90% decrease for total distance, number of movements, and the ratio of total distance to the number of movements occurred, respectively. The hypokinetic effect of S-adenosyl-L-methionine was dose dependent. A 65.0 and 51.3% decrease in total distance and number of movements, respectively, were observed following 9.38 x 10(-9) mol. The 5.0 x 10(-8) mol caused a reduction of 73.42 and 57.66% and 4.0 x 10(-7) mol/rat caused a 94.9 and 78.43% decrease, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:S-adenosyl-L-methionine decreases motor activity in the rat: similarity to Parkinson's disease-like symptoms. 850 24

The multistep assay of specific catechol-O-methyltransferase (COMT) activity in human erythrocytes was validated. Enzyme preparations from lysed erythrocytes were incubated with a substrate (3,4-dihydroxybenzoic acid) in the presence of Mg2+ and S-adenosylmethionine. The reaction products (vanillic acid and isovanillic acid) were analyzable by HPLC with electrochemical detection directly in the incubation medium after protein precipitation. The precision was calculated in order to define the random variability associated with the method by intra-assay and inter-assay relative standard deviations (RSDs) for the assays of both reaction products and protein. The intra-assay RDSs for the specific activities were between 4.8 and 11.9% (n = 5-6) at two levels of COMT activity. The inter-assay RSDs were between 6.4 and 14.2% (n = 5-6), respectively. The total variation was mostly caused by the protein assay and the HPLC assay, and contributions from the sample preparation and incubation steps were minor. Some results from the clinical application of the erythrocyte COMT assay are also reported. For both normal volunteers and patients having Parkinson's disease, a single 400 mg dose of entacapone, a peripherally acting COMT inhibitor, decreased the erythrocyte COMT activity. The application demonstrates that the assay was able to detect differences between the subjects and the effect of COMT inhibition in the clinical study.
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PMID:Validation of assay of catechol-O-methyltransferase activity in human erythrocytes. 873 81

The major symptoms of Parkinson disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by the degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal DA terminals. Norepinephrine (NE) and serotonin (5-HT) levels in the neostriatum and tyrosine hydroxylase and melanin pigments in the substantia nigra are also decreased, and brain cholinergic activity is increased. The cause of PD is unknown, but PD is an age-related disorder, suggesting that changes that occur during the aging process may help to precipitate PD. Methylation increases in aging animals. Increased methylation can deplete DA, NE, and 5-HT; increase acetylcholine; and cause hypokinesia and tremors. These effects are similar to changes seen in PD, and interestingly also, they are similar to some of the changes that are associated with the aging process. It is suggested, therefore, that increased methylation may be an inducing factor in parkinsonism. Accordingly, the effects of an increase in methylation in the brain of rats were studied. S-adenosylmethionine (AdoMet), the limiting factor in the methylation process, was injected into the lateral ventricle of rats. Specific behavioral changes that resemble changes seen in PD were investigated. The results showed that AdoMet caused tremors, rigidity, hypokinesia, and depleted DA. The hypokinetic effects of a single dose of AdoMet lasted for about 90 min. AdoMet has a dose-dependent hypokinetic effect. A dose of 9.4 nmol reduced movement time (MT) by 68.9% and increased rest time (RT) by 20.7%, and a dose of 400 nmol reduced MT by 92.4% and increased RT by 27.6%. The normethyl analog of AdoMet, S-adenosylhomocysteine, did not cause hypokinesia or tremors, but it blocked the AdoMet-induced motor effects. L-dopa, the precursor of DA, also blocked the AdoMet-induced motor effects. These data suggest that the methyl group of AdoMet as well as DA depletion are involved in the AdoMet-induced motor effects. A dose of 0.65 mumol of AdoMet depleted DA in the ipsilateral caudate nucleus (CN) or neostriatum by 50.1%, and DA in the contralateral CN was reduced by 9.3%. Double the dose of AdoMet did not increase the depletion of DA on the ipsilateral CN, but DA in the contralateral CN was decreased by 26.3%. Taken together, the results suggest that increased methylation may contribute to the symptoms of PD.
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PMID:Striatal dopamine depletion, tremors, and hypokinesia following the intracranial injection of S-adenosylmethionine: a possible role of hypermethylation in parkinsonism. 874 29

S-Adenosylmethionine is an essential ubiquitous metabolite central to many biochemical pathways, including transmethylation and polyamine biosynthesis. Reduced CSF S-adenosylmethionine levels in Alzheimer's disease have been reported; however, no information is available regarding the status of S-adenosylmethionine or S-adenosylmethionine-dependent methylation in the brain of patients with this disorder. S-Adenosylmethionine concentrations were measured in postmortem brain of 11 patients with Alzheimer's disease. We found decreased levels of S-adenosylmethionine (-67 to -85%) and its demethylated product S-adenosylhomocysteine (-56 to -79%) in all brain areas examined (cerebral cortical subdivisions, hippocampus, and putamen) as compared with matched controls (n = 14). S-Adenosylmethionine and S-adenosylhomocysteine levels were normal in occipital cortex of patients with idiopathic Parkinson's disease (n = 10), suggesting that the decreased S-adenosylmethionine levels in Alzheimer's disease are not simply a consequence of a chronic, neurodegenerative condition. Reduced S-adenosylmethionine levels could be due to excessive utilization in polyamine biosynthesis. The severe reduction in levels of this essential biochemical substrate would be expected to compromise seriously metabolism and brain function in patients with Alzheimer's disease and may provide the basis for the observations of improved cognition in some Alzheimer's patients following S-adenosylmethionine therapy.
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PMID:Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. 875 43

L-Dopa is the most effective drug known for the treatment of Parkinson's disease. However, the large doses required to treat this neurodegenerative disorder can significantly affect tissue concentrations of sulfur amino acid metabolites due to peripheral and central O-methylation. These effects include decreases in tissue concentrations of the biochemical methyl donor S-adenosylmethionine (SAM), increases in tissue concentrations of the methylation inhibitor S-adenosylhomocysteine (SAH), and increases in plasma concentrations of homocysteine, recently identified as an independent risk factor for vascular disease. In the present study, the ability of the catechol-O-methyltransferase inhibitor Ro 41-0960 to prevent L-Dopa-induced changes in SAM, SAH, and homocysteine concentrations was determined in rats. Rats were injected intraperitoneally with Ro 41-0960 or vehicle 30 min prior to an intraperitoneal injection of L-Dopa or vehicle. One hour after the second injection, the rats were killed and their brains, livers, spleens, kidneys, and plasma collected. SAM and SAH concentrations were then determined in discrete brain regions and peripheral tissues, and total homocysteine concentrations were determined in plasma. In the rats treated with only L-Dopa, decreased SAM concentrations and increased SAH concentrations were found in all brain regions and peripheral tissues measured, and increased homocysteine concentrations were found in plasma, consistent with previous reports. In rats pretreated with Ro 41-0960, however, these L-Dopa-induced effects on sulfur amino acid metabolite concentrations were attenuated or prevented entirely. It remains to be determined if this sparing effect of Ro 41-0960 on sulfur amino acid metabolites has clinical significance.
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PMID:Effect of L-Dopa and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats. 903 74

In the present study, levels of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in whole blood as well as L-methionine S-adenosyltransferase (MAT) activity in erythrocytes were assayed in a series of 20 patients with Parkinson's disease and 12 healthy control subjects. A significant difference was found with regard to SAM levels between patients and controls, with the detected levels being 383.1 +/- 41.5 nM for the parkinsonian patients and 680.6 +/- 30.9 nM for the controls. With regard to SAH, we found no difference between the groups. The catalytic activity of MAT was increased by 30% in patients compared to controls, with the Vmax for methionine being 17.9 +/- 3.7 and 13.9 +/- 2.2 pmol/mg/h, respectively.
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PMID:Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson's disease. 921 94


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