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)

In the cerebrospinal fluid of the patients with Parkinson's disease treated with L-DOPA, L-3-O-methyldopa was the major metabolite of administered L-DOPA. Using a dopaminergic cell model, clonal rat phenochromocytoma PC 12h cells, and by microdialysis of the rat striatum it was proved that L-3-O-methyldopa was taken up into monoamine neurons by transport system specific for aromatic L-amino acids and inhibited transport of L-DOPA and other amino acids competitively. L-3-O-Methyldopa depleted allosteric regulation of the biopterin cofactor on activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis. Depletion of the allostery may perturb the buffer action of endogenous L-DOPA synthesis that stabilizes dopamine level in the brain. By these mechanisms L-3-O-methyldopa may reduce clinical effectiveness of administered L-DOPA and be involved in wearing-off phenomenon. L-DOPA inhibited the activity of tryptophan hydroxylase and thus serotonin synthesis, which may be related to psychiatric side-effects in the patients under L-DOPA therapy.
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PMID:The mechanism of perturbation in monoamine metabolism by L-dopa therapy: in vivo and in vitro studies. 136 50

The activity of tryptophan hydroxylase was measured in nine regions of human brains from controls and patients with Parkinson's disease, striatonigral degeneration, Shy-Drager syndrome and progressive supranuclear palsy by high performance liquid chromatography with fluorescence detection. The regional distribution of the enzyme activity in control brains was similar to that of serotonergic neurons; relatively high activity was found in the raphe nucleus, locus coeruleus and substantia nigra. The activity in the thalamus in Parkinson's disease and that in the locus coeruleus, raphe nucleus and substantia nigra in striato-nigral degeneration were significantly lower than that of controls (p less than 0.05). In most other brain regions in parkinsonian patients the activity was relatively lower than that of controls except the caudate nucleus and nucleus accumbens where the activity was relatively higher than that of controls. Marked decrease in the enzyme activity in various brain regions was observed in striato-nigral degeneration, Shy-Drager syndrome, and progressive supranuclear palsy. These results suggest that the activity of tryptophan hydroxylase in serotonergic neurons is reduced in the brains of parkinsonian patients and of patients with degenerative nervous diseases.
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PMID:Tryptophan hydroxylase activity in the brains of controls and parkinsonian patients. 402 Mar 80

The involvement of abdominal afferent vagal activity and serotonergic mechanisms were examined following intravenous administration of talipexole, a dopamine D2 receptor agonist used for treatment of Parkinson's disease, in anesthetized rats. Intravenous administration of dopamine receptor agonists including D1/D2 components increased the spontaneous firing of afferent vagal neurons as did 2-methyl-5-hydroxytryptamine. Both talipexole (0.25-1.0 mg/kg) and bromocriptine (1.0-10.0 mg/kg) increased vagal nerve activity in a dose-dependent manner, and the effect of 10 mg/kg of bromocriptine was significantly greater than that noted with 1.0 mg/kg of talipexole. Increasing vagal firing induced by talipexole was prevented by pretreatment with granisetron, but not with metoclopramide or by spinal section, indicating that afferent vagal firing was mediated via stimulation of the 5-HT3 receptors on the neurons and secondarily caused by stimulation of dopamine receptors. On the other hand, bromocriptine at 5 mg/kg increased 5-HIAA concentration in the ileum, and serotonin turnover (5-HIAA/5-HT) was increased approximately 4-fold when compared to the vehicle group. Bromocriptine also increased the activities of tryptophan hydroxylase and monoamine oxidase. Talipexole at 0.5 mg/kg did not affect ileal 5-HT metabolism and the enzymatic activities. These findings suggest that dopamine receptor agonists may induce changes in abdominal afferent vagal activity and ileal 5-HT metabolism similar to those observed with emetic compounds, and that talipexole has a much smaller influence on serotonin-mediated responses than does bromocriptine with equipotent antiparkinsonian doses. One of the possible reason why talipexole showed fewer emetic side effects in patients with Parkinson's disease may be that the emetic responses triggered by D2 receptor stimulation may secondarily cause an increase of abdominal afferent vagal activity, which may be weakened by the 5-HT3 receptor antagonistic property of talipexole.
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PMID:Effects of talipexole on emesis-related changes in abdominal afferent vagal activity and ileal serotonin metabolism in rats. 905 50

Tryptophan hydroxylase, the initial and rate limiting enzyme in the biosynthesis of serotonin (5-HT), is inactivated by the quinone of L-DOPA. L-DOPA itself has no effect on enzyme activity. The inactivation of tryptophan hydroxylase could be prevented by glutathione (GSH), dithiothreitol, cysteine, and ascorbic acid but not by scavengers of hydrogen peroxide (catalase), hydroxyl radical (DMSO), or superoxide (superoxide dismutase). All cysteinyl residues within tryptophan hydroxylase are modified after treatment with L-DOPA-quinone as revealed by loss of DTNB-reactivity and formation of cysteinyl-DOPA residues. L-DOPA-quinone also converts tryptophan hydroxylase to a redox-cycling quinoprotein. These results suggest a possible mechanism of 5-HT neuronal damage in Parkinson's Disease by a redox-cycling quinoprotein.
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PMID:L-DOPA-quinone inactivates tryptophan hydroxylase and converts the enzyme to a redox-cycling quinoprotein. 1058

Tryptophan hydroxylase is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin. A variety of drugs are known to diminish the function of this enzyme, and possibly cause damage to serotonin neurons. These include the substituted amphetamines methamphetamine and 3,4-methylenedioxy-methamphetamine, as well as L-DOPA, the most common therapy for Parkinsons Disease. In view of the important role for dopamine in the effects of these drugs on tryptophan hydroxylase and on serotonin neurons, we tested whether dopamine could alter the activity of this important enzyme. We found that dopamine-derived quinones, but not dopamine, inactivate tryptophan hydroxylase and convert the protein to a redox-cycling quinoprotein. This posttranslational modification of tryptophan hydroxylase could play a role in the drug-induced reduction in serotonin synthesis.
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PMID:Tryptophan hydroxylase regulation. Drug-induced modifications that alter serotonin neuronal function. 1072 Oct 34

It has recently been reported that the human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme), but not for tyrosine hydroxylase (TH; the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH; the first-step serotonin synthesizing enzyme). These AADC (+)/TH(-)/TPH(-) neurons are named D-neurons. AADC is also the rate-limiting synthesizing enzyme of phenylethylamine (PEA). Although the functions of striatal D-neurons are yet unclear, their functions were discussed in the present review based on recent findings in the literature. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors, including L-dopa or droxidopa (L-threo-DOPS), and by converting them to dopamine (DA) or noradrenaline (NA), respectively. Because the nucleus accumbens is one of the brain regions involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration. Further studies should be conducted to elucidate the functions of this unique cell group in the human striatum.
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PMID:[Human striatal D-neurons and their significance]. 1237 66

Neurodegenerative diseases share symptoms suggested to be related to the serotonergic system. To evaluate the involvement of serotonergic raphe nuclei, we compared the percentage of neurons synthesizing serotonin in the nucleus centralis superior (NCS), raphe obscurus and pallidus (NROP) in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Parkinson's disease (PD), multiple system atrophy (MSA), and control brains. We used immunohistochemistry for tryptophan hydroxylase (TpOH), phosphorylated tau, and alpha-synuclein. We observed a significant decrease in the NCS in the NROP in AD, but a significant increase in PSP and MSA. Cytoskeletal pathology was present in the NCS and NROP to a variable degree. We conclude that there is disease- and nucleus-specific alteration of serotonin synthesis in the raphe.
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PMID:Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders. 1254 34

It has recently been reported that the human corpus striatum, especially its ventral part, named as the nucleus accumbens, contains numerous non-monoaminergic aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme) neurons (D-neurons). D-neurons are the neurons immunoreactive for AADC but not immunoreactive for dopamine or serotonin. They lack the first-step monoamine synthesizing enzymes, tyrosine hydroxylase and tryptophan hydroxylase. AADC is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons might participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors including L-dopa or droxidopa (L-threo-DOPS) and by converting them to dopamine or noradrenaline, respectively. As the nucleus accumbens is one of the brain regions that are involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration.
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PMID:[Localization of non-monoaminergic aromatic L-amino acid decarboxylase neurons (D-neurons) in the human striatum and their functional significance]. 1255 14

We sought to determine whether medullary serotonergic neurons were affected in multiple system atrophy (MSA). Immunostaining for tryptophan hydroxylase was performed on serial 50 microm sections of the medulla of brains obtained at autopsy from six control subjects, eight subjects with clinical diagnosis of MSA, and four with Parkinson's disease. There was a severe depletion of serotonergic neurons in the nucleus raphe magnus, raphe obscurus, raphe pallidus, and ventrolateral medulla in MSA. Depletion of serotonergic neurons may contribute to impaired control of sympathetic outflow and other abnormalities in MSA.
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PMID:Involvement of medullary serotonergic groups in multiple system atrophy. 1499 20

Previously, this laboratory has shown that human foetal progenitor cells derived from ventral mesencephalon (VM) can be developmentally directed towards a dopaminergic lineage. In the present study, the effects are reported of several as yet untested differentiation/survival factors on the controlled conversion of neural progenitor cells to dopaminergic neurons. Positive immunoreactivity to tyrosine hydroxylase (TH) and raised levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), secreted into culture medium, were used to indicate the presence of the dopaminergic neuronal phenotype, i.e., active TH. Incubation with retinoic acid (RA) (0.5 microM) lead to an increase in the number of cultured cells showing positive immunoreactivity for the neuronal marker, microtubule-associated protein (MAP)-2ab. A concomitant increase in TH-positive immunoreactivity was also demonstrated. The brain-derived neurotrophic factor (BDNF) (50 ng/ml), glial-derived neurotrophic factor (GDNF) (10 ng/ml) and interleukin-1 beta (IL-1 beta) (10 ng/ml) also had positive effects in promoting neural progenitor cell differentiation towards the dopaminergic phenotype in the presence of dopamine (10 microM) and forskolin (Fsk) (10 microM). There was no synergy in this effect when progenitor cells were incubated with all of these agents simultaneously. The trans-differentiation potential of the progenitor cells to be directed towards other neurotransmitter phenotypic lineages was also investigated. It was found that, with the right cocktails of agents, serotonin (Ser) (75 microM), acidic fibroblast growth factor (aFGF) (10 ng/ml), BDNF (50 ng/ml) and forskolin (10 microM), these same cells could be directed down the serotonergic cell lineage pathway (as judged by the appearance of tryptophan hydroxylase (TPH) positive immunoreactivity, and synthesis of 5-HT and its metabolites, secreted into the culture medium). However, no cocktail containing noradrenaline (10 nM-500 microM), BDNF (50 ng/ml) and forskolin (10 microM) was found which promoted differentiation towards the noradrenergic cell phenotype as judged by the absence of any TH or D beta H positive immunoreactivity, and no formation of 3,4-dihydroxyphenylethyleneglycol (DOPEG), the principal metabolite of noradrenaline. The controlled trans-differentiation potential of these cell could pave the way for development and harvesting of large numbers of neurons of the appropriate neurotransmitter phenotype for future transplantation therapies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease.
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PMID:The differentiation potential of human foetal neuronal progenitor cells in vitro. 1546 16


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