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)

Human manganese poisoning or manganism results in damage to the substantia nigra of the brain stem, a drop in the level of the inhibitory neurotransmitter dopamine, and symptoms resembling those of Parkinson's disease. Manganic (Mn3+) manganese ions were shown to be readily produced by O-2 in vitro and spontaneously under conditions obtainable in the human brain. Mn3+ as its pyrophosphate complex was shown to rapidly and efficiently carry out four-electron oxidations of dopamine, its precursor dopa (3,4-dihydroxyphenylalanine), and its biosynthetic products epinephrine and norepinephrine. Mn3+-pyrophosphate was shown to specifically attack dihydroxybenzene derivatives, but only those with adjacent hydroxyl groups. Further, the addition of Mn2+-pyrophosphate to a system containing a flux of O2- and dopamine greatly accelerated the oxidation of dopamine. The oxidation of dopamine by Mn3+ neither produced nor required O2, and Mn3+ was far more efficient than Mn2+, Mn4+ (MnO2), O2-, or H2O2 in oxidizing the catecholamines. A higher oxidation state, Mn(OH)3, formed spontaneously in an aqueous Mn(OH)2 precipitate and slowly darkened, presumably being oxidized to MnO2. Like reagent MnO2, it weakly catalyzed dopamine oxidation. However, both MnO2 preparations showed dramatically increased abilities to oxidize dopamine in the presence of pyrophosphate due to enhancement of the spontaneous formation of the Mn3+ complex. These results strongly suggest that the pathology of manganese neurotoxicity is dependent on the ease with which simple Mn3+ complexes are formed under physiological conditions and the efficiency with which they destroy catecholamines.
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PMID:Manganese poisoning and the attack of trivalent manganese upon catecholamines. 303 17

Tyrosine and tryptophan have been assayed spectrofluorometrically in postmortem human brain areas of patients with Parkinson's disease treated orally with or without 3,4-dihydroxyphenylalanine (L-dopa) plus the peripherally acting decarboxylase inhibitor benserazide. Tyrosine as well as tryptophan decrease significantly after treatment with L-dopa, thus showing a competitive action of L-dopa to other aromatic amino acids on human brain uptake. It is suggested that some of the side effects of L-dopa treatment in Parkinson's disease are due to a disturbance in the brain and neural uptake of other, specially aromatic and branched-chain amino acids. An influence of L-dopa administration on protein synthesis also cannot be excluded.
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PMID:L-dopa competes with tyrosine and tryptophan for human brain uptake. 721 1

Previous studies have used recombinant retroviruses encoding the tyrosine hydroxylase (TH) gene to transduce various cell lines, including fibroblasts (NIH-3T3), a pituitary tumor cell line (AtT20), and a pancreatic endocrine line (RIN). These genetically modified cells, synthesizing either 3,4-dihydroxyphenylalanine, dopamine, or both, are potential donors for treatment of Parkinson's disease. However, the levels of TH protein in such transduced cells have been low and heterogeneous. Using several modified versions of retrovirus vectors encoding TH, we demonstrated that protein stability is an important factor governing levels of TH in NIH-3T3 fibroblasts. Whereas low levels of TH protein were observed in infected NIH-3T3 cells, high levels of a TH-beta gal fusion protein were found. This difference was due to a significantly longer half-life of the TH-beta gal fusion protein relative to TH alone. However, the TH-beta gal fusion protein was found to be enzymatically inactive. We also found that the half-life of the endogenous TH protein in PC-12 cells is sevenfold longer than the TH protein in transduced fibroblasts, implying that a cell-type specific regulator or mechanism may stabilize TH in catecholaminergic cells.
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PMID:The stability of endogenous tyrosine hydroxylase protein in PC-12 cells differs from that expressed in mouse fibroblasts by gene transfer. 750 76

One therapeutic approach to treating Parkinson's disease is to convert endogenous striatal cells into levo-3,4-dihydroxyphenylalanine (L-dopa)-producing cells. A defective herpes simplex virus type 1 vector expressing human tyrosine hydroxylase was delivered into the partially denervated striatum of 6-hydroxydopamine-lesioned rats, used as a model of Parkinson's disease. Efficient behavioral and biochemical recovery was maintained for 1 year after gene transfer. Biochemical recovery included increases in both striatal tyrosine hydroxylase enzyme activity and in extracellular dopamine concentrations. Persistence of human tyrosine hydroxylase was revealed by expression of RNA and immunoreactivity.
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PMID:Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. 763 5

Ever since the introduction of levo-3,4-dihydroxyphenylalanine (L-dopa) for the treatment of Parkinson's disease, there has been concern that it might accelerate the degeneration of dopamine neurones. Using rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB), we have studied the effect of chronic L-dopa treatment on the survival of dopamine cells which remain in the ventral tegmental area (VTA) ipsilateral to a 6-OHDA lesion. Following lesion surgery, rats were treated with L-dopa and carbidopa administered in the drinking water for 27 weeks. At the end of the treatment period, the number of dopamine cells remaining in each of the lesioned and intact substantia nigra (SN) and VTA were assessed, using tyrosine hydroxylase immunohistochemistry. Chronic L-dopa treatment resulted in an apparent reduction in the number of dopamine neurones remaining in the VTA ipsilateral to the lesion, whereas it had no effect on the number of dopamine cells remaining in the intact SN and VTA. This finding suggests a possible suppressive effect in vivo of L-dopa on dopamine cells in the midbrain of adult animals that have been previously exposed to 6-OHDA.
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PMID:Suppressive effect of L-dopa on dopamine cells remaining in the ventral tegmental area of rats previously exposed to the neurotoxin 6-hydroxydopamine. 809 79

Ten free monoamines and their metabolites in plasma and cerebrospinal fluid (CSF) were simultaneous measured in 6 levodopa-untreated (LU), 18 levodopa-treated (LT) and 37 levodopa-withdrawn (LW) Chinese patients with Parkinson's disease (PD) and 26 controls. We found that the levels of these substances in LW patients were not significantly different from those in LU patients. In LU- and LW-PD patients, CSF epinephrine (EPI) was higher (P < 0.05) than that of the controls. 3-methoxy-DOPA (3-OMDOPA) might not inhibit the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and dopamine metabolites in CSF. Levodopa treatment might change the dopaminergic and serotoninergic neuronal systems, but not the noradrenergic or adrenergic neuronal systems, in CNS of PD patients. Benserazide (a peripheral decarboxylase inhibitor) in Madopar might decrease the levels of serotonin (5-HT) and norepinephrine (NE), but not those of DOPA and homovanillic acid (HVA), in plasma. HVA, NE and EPI in plasma were not good indices for those in CSF. Otherwise, our results were consistent with some other studies by showing a significantly lower level (P < 0.01) of HVA in CSF of LU- and LW-PD patients than that of the controls, while no difference for NE, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindole acetic acid (5-HIAA) or 3-OMDOPA was noted. The severity of clinical disability was related to the deficiency of CSF HVA and DOPAC in LU- and LW-PD patients; however, there was no relationship between clinical symptoms of tremor, rigidity-bradykinesia, autonomic dysfunction, dementia, depression or levodopa-induced dyskinesia and CSF monoamines or their metabolites.
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PMID:Monoamines and their metabolites in plasma and lumbar cerebrospinal fluid of Chinese patients with Parkinson's disease. 833 58

Autoxidation of dopamine or L-DOPA (3,4-dihydroxyphenylalanine) generates reactive oxygen species (ROS), i.e., hydrogen peroxide, superoxide, and hydroxyl radical, which are potentially cytotoxic. Increased formation of ROS has been proposed to be involved in the pathogenesis of many human diseases, including Parkinson's disease. Several reports suggest that R(-)-deprenyl (an MAO-B inhibitor and anti-Parkinsonian drug) may directly or indirectly exert antioxidant effects and thus protect neurons. We have assessed the toxic effects of dopamine and L-DOPA toward catecholaminergic neuroblastoma SH-SY5Y cells and whether R(-)-deprenyl and several structurally related compounds possess antioxidant effects in this system. The results show that both dopamine and L-DOPA are quite cytotoxic toward SH-SY5Y cells. R(-)-deprenyl rather than reducing this dopamine-induced toxicity actually enhances it. Structural analogues of R(-)-deprenyl, such as 4-methyldeprenyl, (-)-methylamphetamine, and clorgyline, exhibited similar effects. Some different MAO-B inhibitors, namely, the aliphatic N-methylpropargylamines, e.g., (+/-)-M-2-PP [N-(2-pentyl)-N-methylpropargylamine] and N-[2-hexyl]-N-methylpropargylamine, which can also protect and rescue neurons in several in vivo and in vitro models, did not exacerbate the cytotoxicity of dopamine. Neither R(-)-deprenyl nor (+/-)-M-2-PP affected the L-DOPA-induced cytotoxicity toward SH-SY5Y cells.
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PMID:R(-)-deprenyl potentiates dopamine-induced cytotoxicity toward catecholaminergic neuroblastoma SH-SY5Y cells. 900 48

Ascorbic acid is well known to induce noradrenaline synthesis in sympathetic nervous cells. In a series of experiments we found that incubation of the neuroblastoma cell line SK-N-SH with ascorbic acid (100-500 microM) for 2 h results in a significantly enhanced synthesis of 3,4-dihydroxyphenylalanine (DOPA) and dopamine. Additionally, cDNA-polymerase chain reaction (cDNA-PCR) analysis of relative mRNA levels corresponding to the enzymes involved in catecholamine synthesis revealed a 3-fold increase of tyrosine hydroxylase gene expression after 5 days of incubation with ascorbic acid (200 microM), whereas expression of dopamine-beta-hydroxylase was found to be unaltered. In summary the data give evidence that ascorbic acid leads to enhanced DOPA production in SK-N-SH cells by two different mechanisms: at the metabolic level after short-term incubation and by increasing the tyrosine hydroxylase gene expression after long-term incubation. Based on these data we suppose that enhancement of DOPA synthesis by ascorbic acid may be useful in the treatment of early Parkinson's disease.
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PMID:Ascorbic acid stimulates DOPA synthesis and tyrosine hydroxylase gene expression in the human neuroblastoma cell line SK-N-SH. 957 38

The potential of a novel therapeutic approach for treating Parkinson's disease, which involves the transplantation of a transfected human astrocyte cell line SVG-TH, that stably expresses the rate-limiting enzyme for dopamine production, tyrosine hydroxylase, was examined. SVG-TH and untransfected parent cells were grafted into the diseased striatum of rats in which Parkinson's disease had been induced by the administration of 6-hydroxydopamine. The in situ production and spillover of 3,4-dihydroxyphenylalanine (the precursor of dopamine), dopamine and their metabolites in the striatal extracellular fluid of the grafted rats was determined in conscious animals using the microdialysis technique and a high pressure liquid chromatography apparatus. Alleviation of symptoms of Parkinson's disease (abnormal movements) was evaluated by rotation tests. Upon transplantation of the SVG-TH cells into the striatum of the parkinsonian rats, the levels of dopamine in extracellular fluid of the striatum reached those of the normal rats, and correlated well with the improvement (74%) in their rotating behaviour (behavioural deficit). The levels of the two main dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, were low in the lesioned rats, even after SVG-TH transplantation. An alternative route of metabolism of dopamine may occur in the transplanted striatum, since the dopamine metabolite, 3-O-methoxy-4-hydroxy-phenylethylamine, appeared, which indicates activity of catechol-O-methyl transferase. Upon blockade of L-aromatic-amino acid decarboxylase, 3,4-dihydroxyphenylalanine accumulated in extracellular fluid of the 6-hydroxydopamine-lesioned and SVG-TH-grafted rats, which indicated that these cells produced active tyrosine hydroxylase in vivo. These findings indicate the potential of treating Parkinson's disease by the intrabrain grafting of human astrocyte cells transfected with the rate limiting enzyme for dopamine production.
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PMID:Dopamine turnover and metabolism in the striatum of parkinsonian rats grafted with genetically-modified human astrocytes. 962 40

We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, using in vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DA synthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DA release. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.
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PMID:Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum. 987 42


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