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)

Tremor is the most visible symptom of Parkinson's Disease (PD), and should be the appropriate parameter in models for its evaluation. Lack of reliable PD tremor models and methods to distinguish tremors from nontremor movements means that nontremor behavior such as rotation following basal ganglia damage are mostly used. Our laboratory has shown that S-adenosyl-methionine (SAM) injections into the brain of rats reliably produced tremors, rigidity, hypokinesia, and abnormal posture. Thus, SAM-induced tremors, when distinguished from nontremor activities, has the potential as a model for testing anti-PD agents. Tremor Monitor-recorded activity profiles of the rats injected with SAM showed low-amplitude signals interlaced with high-amplitude bursts of tremor episodes. Control activities were of low-medium amplitudes with no such patterns. The number of real and apparent episodes detected over 20 min were 92 +/- 12 and 84 +/- 14 lasting 470 +/- 50 and 210 +/- 50 s, indicating mean durations of 5.1, and 2.4 s, frequencies of 12 +/- 0.1 and 11 +/- 0.2 Hz, cycles (waves) per episode of 54 +/- 6 and 19 +/- 2 and amplitudes of 42.3 +/- 5 and 19.8 +/- 1 for the SAM-treated and control rats, respectively. The nontremor activities of rats injected with phosphate-buffered saline were distinguished and eliminated by raising the minimum amplitude and number of cycles to 20. This procedure is being enhanced for screening antitremor agents and for elucidating the possible mechanism for Parkinsonism.
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PMID:Quantification of S-adenosylmethionine-induced tremors: a possible tremor model for Parkinson's disease. 1068 94

The effects of L-dopa on methylation process in the mouse brain were investigated. The study is based on recent findings that methylation may play an important role in Parkinson's disease (PD) and in the actions of L-dopa. The methyl donor, S-adenosylmethionine (SAM) and a product of SAM, methyl beta-carboline, were shown to cause PD-like symptoms, when injected into the brain of animals. Furthermore, large amounts of 3-O-methyl dopa, the methyl product of L-dopa, are produced in PD patients receiving L-dopa treatment, and L-dopa induces methionine adenosyl transferase, the enzyme that produces SAM. The results show that, at 0.5 hr, L-dopa (100 mg/kg) decreased the methyl donor, S-adenosylmethionine (SAM) by 36%, increased its metabolite S-adenosylhomocysteine (SAH) by 89% and increased methylation (SAH/SAM) by about 200%. All parameters returned to control values within 4 hr. But 2, 3 and 4 consecutive injections of L-dopa, given at 45 min intervals, depleted SAM by 60, 64 and 76% and increased SAM/SAH to 818, 896, and 1524%. L-dopa (50, 100 and 200 mg/kg) dose-dependently depleted SAM from 24.9 +/- 1.7 nmol/g to 13.0 +/- 0.8, 14.7 +/- 0.8 and 7.7 +/- 0.7 nmol/g, and increased SAH from 1.88 +/- 0.14 to 3.43 +/- 0.26, 4.22 +/- 0.32 and 6.21 +/- 0.40 nmol/g. Brain L-dopa was increased to 326, 335 and 779%, dopamine to 138, 116 and 217% and SAH/SAM to 354, 392 and 1101%. The data show that L-dopa depletes SAM, and increases methylation 4-5 times more than dopamine, therefore, methylation may play a role in the actions of L-dopa. This and other studies suggest that the high level of utilization of methyl group by L-dopa leads to the induction of enzymes to replenish SAM and to increase the methylation of L-dopa as well as DA. These changes may be involved in the side effects of L-dopa.
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PMID:Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa. 1085 49

In a previous paper, it was suggested that a relative deficiency of essential fatty acids might play a role in the etiology of sporadic or non-familial Alzheimer's disease. A recent article regarding dementia in the Rotterdam Study reinforces this suggestion. It is also hypothesized that this relative deficiency could facilitate passage of aluminum into the brain, aluminum being increasingly suggested as one of the possible pathogenic factors in AD. It is further suggested that hypomethylation caused by a deficiency of S-adenosylmethionine might also play a role in the etiology of this disease and perhaps even of Parkinson's disease.
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PMID:Alzheimer's disease revisited. 1085 85

Injection of the endogenous methyl donor, S-adenosyl methionine (SAM), into rat brain induces Parkinson's disease (PD)-like symptoms possibly by stimulating deleterious protein methylation. Gel-filtration chromatography of rat brain extracts treated with [3H-methyl]-SAM revealed the presence of radioactive peaks with apparent molecular weights of about 5 kDa. Treatment with guanidine HCl altered the elution volumes of the labeled peaks. Lyophilized peak fractions released volatile 3H-methanol on incubation with NaOH, indicating the presence of carboxyl methyl esters. Because prenylated proteins are avid methyl acceptors at the terminal carboxylic acid groups, 1 micromol S-farnesylcysteine (FC) analogs blocked the SAM-induced tremors in the experimental rats. FC analogs did not only reverse the associated rigidity, abnormal posture, and hypokinesia, but stimulated hyperactivity in the animals. This amphetamine-like effect was monitored for 20 min in an animal activity monitor and movement times between 400 +/- 100 and 560 +/- 125 s covering distances between 78 +/- 29 to 125 +/- 35 m were recorded for rats treated with FC analogs with or without SAM. Control animals moved only for 60 +/- 13 s covering about 6 +/- 1 m, indicating a 7-9-fold and 13-21-fold increase in duration of movement and distance covered, respectively. N-Acetyl-S-farnesylcysteine (AFC) potentiated amphetamine-induced ipsiversive rotation of 6-hydroxydopamine-lesioned rats from 390 +/- 130 to 830 +/- 110, with AFC alone having no significant effect on net rotation compared to controls. These data indicate that intracerebroventricular injection of SAM may induce PD symptoms by interfering with the methylation/demethylation homeostasis of prenylated proteins that function in the dopaminergic and other signaling pathways, and that the FC analogs may counteract the SAM effects by acting synergistically on events subsequent to neurotransmitter release.
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PMID:Farnesyl-L-cysteine analogs block SAM-induced Parkinson's disease-like symptoms in rats. 1097 24

We report a pilot study of S-adenosyl-methionine (SAM) in 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAM was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale (HDS). One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean HDS score before treatment was 27.09 +/- 6.04 (mean +/- standard deviation) and was 9.55 +/- 7.29 after SAM treatment (p < 0.0001). Although uncontrolled and preliminary, this study suggests that SAM is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease.
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PMID:S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. 1110 10

Levodopa is administered with dopa decarboxylase inhibitors (DDI) to prevent its peripheral degradation. This increases conversion of levodopa to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). S-adenosylmethionine (SAM), which is synthesized from adenosine triphosphate and methionine (MET), serves as methyl donor for this O-metabolisation of levodopa with resulting conversion of SAM to total homocysteine (tHcy) via S-adenosylhomocysteine (SAH). Previous studies showed augmented plasma levels of tHcy in long-term levodopa/DDI-treated patients with Parkinson's disease (PP). Objective of this study was to compare MET, SAM, levodopa, 3-OMD, tHcy and SAH in plasma of 20 levodopa/DDI treated PP and corresponding controls. A significant decrease of MET respectively SAM and an increase of tHcy appeared in PP. SAH with its short half-life did not differ. Levodopa/DDI long-term treatment contributes to altered levels of substrates of the O-methylation cycle in PP.
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PMID:Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease. 1144 84

Our previous studies showed that S-adenosyl-methionine (SAM) induced Parkinson's disease-like changes in rat. It caused death to dopamine neurons in the substantia nigra, which appeared shrunken and fragmented, indicative of apoptosis-like changes (Charlton and Crowell [1995] Mol. Chem. Neuropathol. 26:269-284; Charlton [1997] Life Sci. 61:495-502). In this study, we investigated whether SAM causes apoptosis in both undifferentiated PC12 (PC12) cells and nerve growth factor (NGF)-differentiated PC12 (D-PC12) cells. S-adenosyl-homocysteine (SAH), the nonmethyl analog of SAM, was also tested. SAM and SAH (1.0 nM to 10.0 microM) caused lactate dehydrogenase (LDH) release from the PC12 cells and D-PC12 cells; cells with morphological changes and fluorescent DNA fragmentation staining were detected among both PC12 cell and D-PC12 cell. Compared with the PC12 cell, the D-PC12 cell, a postmitotic cell, was more sensitive to the toxic effects of SAM or SAH and presented much greater LDH release, suggesting a lethal effect; surprisingly, the amounts of apoptotic cells did not differ significantly between the two kinds of cells. In medium deprived of exogenous methionine, a decline in LDH release was observed in PC12 and D-PC12 cells. Also, lower levels of intracellular SAM and SAH were observed in the methionine-deleted media, which were reversed by the addition of either SAM or SAH. An antivitamin B(12) monoclonal antibody was added to methionine-depleted medium, resulting in deficiency of both endogenous and exogenous methionine, which caused further decreases in LDH release and reduction in the levels of intracellular SAM and SAH. The preliminary data showed different sensitivities to SAM or SAH between PC12 cell and D-PC12 cells, which suggests that PC12 cell may be more stable as a metabolic model. Apoptosis of PC12 cells was also assessed by PARP cleavage detection, Western blot analysis of Bax and Bcl-2 proteins, and DNA laddering on agarose gel electrophoresis. The proapoptoic protein Bax was dominantly expressed, whereas Bcl-2 was slightly down-regulated by SAM. SAH weakly induced the expression of Bax and slightly decreased Bcl-2 levels. The effects of SAM and its analog, SAH, were demonstrated conclusively to induce apoptosis in PC12 cells.
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PMID:S-adenosyl-methionine-induced apoptosis in PC12 cells. 1221 Aug 45

Inhibition of the enzyme catechol-O-methyltransferase (COMT) is an important approach in the treatment of Parkinson's disease. A series of new potent bisubstrate inhibitors for COMT, resulting from X-ray structure-based design and featuring adenosine and catechol moieties have been synthesised. Biological results show a large dependence of binding affinity on inhibitor preorganisation and the length of the linker between nucleoside and catechol moieties. The most potent bisubstrate inhibitor for COMT has an IC50 value of 9 nM. It exhibits competitive kinetics for the SAM and mixed inhibition kinetics for the catechol binding site. Its bisubstrate binding mode was confirmed by X-ray structure analysis of the ternary complex formed by the inhibitor, COMT and a Mg2+ ion.
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PMID:Bisubstrate inhibitors for the enzyme catechol-O-methyltransferase (COMT): influence of inhibitor preorganisation and linker length between the two substrate moieties on binding affinity. 1292 89

We previously showed that S-adenosylmethionine (SAM) induces movement impairments similar to those observed in Parkinson's disease (PD) apparently by prenylated protein methylation; 5 kDa molecules being methylated and the symptoms being inhibited by prenylcysteine (PC) analogs. In the present study, we explore the biochemical mechanism of action of the PC analogs. N-acetylgeranylcysteine (AGC), N-acetylfarnesylcysteine (AFC), N-acetylgeranylgeranylcysteine (AGGC), farnesylthioacetic acid (FTA), farnesyl-2-ethanesulfonic acid (FTE) and farnesylsuccinic acid (FMS), but not farnesylthiotriazole (FTT) and farnesylthiolactic acid (FTL), inhibited the SAM-induced motor impairments. Incubation of the respective analogs with rat brain membranes containing prenylated protein methyltransferase (PPMTase) resulted in the methylation of AGC, AFC and AGGC. FTA, FTE, FMS and FTT, but not FTL, inhibited the enzyme activity. A single injection of the active analogs remained effective for at least 3 days against repeated injections of 1 micromol SAM. Amphetamine-induced hyperactivity in rats was inhibited by SAM but potentiated by FTE. During 60 min, the movement time for amphetamine-treated rats was 1477 s compared with 633 and 1664 s for amphetamine+SAM- and amphetamine+FTE-treated rats, respectively. The total distance for amphetamine+FTE-treated rats was 82% higher than for amphetamine. The horizontal activity was 30,728 (amphetamine), 15,430 (FTE), 18,526 (amphetamine+SAM), 41,736 (amphetamine+FTE) and 7004 (SAM) as compared to the PBS control (4726). The intricate relationship between the actions of SAM, which speeds up prenylated protein methylation and impairs movement, amphetamine, which increases synaptic dopamine levels and movement, and the PC analogs, which prevent the SAM-induced movement impairments, suggests a SAM-induced defect on dopamine signaling as the likely cause of the symptoms. The data reveal that interaction of PC analogs with PPMTase may not be an indicator of anti-PD-like activity.
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PMID:Inhibition mechanism of S-adenosylmethionine-induced movement deficits by prenylcysteine analogs. 1464 42

Excess methylation has been suggested to play a role in the pathogenesis of Parkinson's disease (PD), since the administration of S-adenosylmethionine (SAM), a biological methyl donor, induces PD-like changes in rodents. It was proposed that SAM-induced PD-like changes might be associated with its ability to react with the dopaminergic system. In the present study the effects of SAM on dopamine receptors and transporters were investigated using rats and cloned dopamine receptor proteins. Autoradiographic examination of SAM indicated its tendency to be localized and accumulated in rat striatal region after the intracerebroventricular injection into rat brain. Moreover, results showed that SAM significantly decreased dopamine D1 and D2 receptor binding activities by decreasing the Bmax and increasing the Kd values. At concentrations of 0.1, 0.25 and 0.5 mM, SAM was able to reduce the Bmax from the control value of 848.1 for dopamine D1-specific ligand [3H] SCH 23390 to 760.1, 702.6 and 443.0 fmol/mg protein, respectively. At the same concentrations, SAM was able to increase the Kd values from 0.91 for the control to 1.06, 3.84 and 7.01 nM of [3H] SCH 23390, respectively. The effects of SAM on dopamine D2 binding were similar to those of dopamine D1 binding. SAM also decreased dopamine transporter activity. The interaction of SAM with dopamine receptor proteins produced methanol from methyl-ester formation and hydrolysis. We propose that the SAM effect might be related to its ability to react with dopamine receptor proteins through methyl-ester formation and methanol production following the hydrolysis of the carboxyl-methylated receptor proteins.
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PMID:The inhibitory role of methylation on the binding characteristics of dopamine receptors and transporter. 1515 79


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