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)

Levodopa, at concentrations of 0.25 x 10(-4) M or larger, is toxic for the human neuroblastoma cell NB69. Toxicity is associated with high levels of quinones, increased activity of complex II-III, and lack of changes of complex I of the mitochondrial respiratory chain. Deprenyl, which does not alter the production of quinones, has a partial protective effect. Tocopherol, 23 or 115 x 10(-6) M, lacks significant preventive effect on levodopa toxicity, but ascorbic acid, 10(-3) M, prevents levodopa toxicity and quinone formation. Deprenyl, 10(-4) M, provides additional protection in cultures treated with levodopa and ascorbic acid. Our results indicate that ascorbic acid and deprenyl prevent levodopa neurotoxicity by unrelated mechanisms. Both compounds should be considered as complementary drugs to test for slowing the progression of Parkinson's disease.
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PMID:Ascorbic acid protects against levodopa-induced neurotoxicity on a catecholamine-rich human neuroblastoma cell line. 834 Dec 91

We have shown that following heat shock (42.5 degree C for 30 min), mouse-derived C1300 N2A neuroblastoma cells contain increased levels of mRNA coding for the inducible form of heat shock protein 70 and for ubiquitin. Incubation of C1300 cells with iron also induces an elevation in content of mRNAs coding for the same two proteins that can be blocked by alpha-tocopherol and desferrioxamine. Iron was shown to increase mitochondrial and lysosomal activities in differentiated C1300 N2A cultures, as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and neutral red cytotoxicity assays. These responses were not initially associated with any loss of viability, as assessed by the lactate dehydrogenase release assay. These results suggest that there is production of cytoprotective heat shock proteins in response to iron-mediated cell damage, probably involving free radical generation, in neural cells. The apparent stress response of vulnerable neurones in human neurodegenerative diseases, particularly Parkinson's disease, may be induced by iron-mediated free radical production in degenerating neurones, making investigation of the mechanism of free radical-induced responses in neuronal cells of special interest.
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PMID:Changes in heat shock protein 70 and ubiquitin mRNA levels in C1300 N2A mouse neuroblastoma cells following treatment with iron. 838 Apr 40

We have previously reported that ciliary neurotrophic factor (CNTF) mRNA is upregulated in the rat striatum following trauma and that its peak is coincident with a peak in the number of GFAP-positive astrocytes. CNTF, or other neurotrophic factors present in the traumatized striatum, may be involved in the dopaminergic fiber sprouting seen following cavitation or graft implantation in animal models of Parkinson's disease. This study was undertaken in order to further characterize the neurotrophic activity present following trauma through the use of bioassays. Adult rats underwent stereotaxic biopsy of the right striatum, and gelatin sponge [gelfoam (GF)] was placed in the resultant cavity. GF was collected from 1 to 30 days following trauma and homogenized. GF extracts (with equal protein concentrations) were assayed using dorsal root ganglion (DRG) explants, dissociated ciliary ganglia (CG), and human dopaminergic neuroblastoma cell (SH-SY5Y) cultures. The GF extracts had significant neurite-promoting activity (NPA) for DRG, CG, and SH-SY5Y cells, with the maximum effect seen 7 days after trauma. NPA was not blocked by anti-nerve growth factor (NGF) Ab, but anti-brain-derived neurotrophic factor (BDNF) Ab significantly blocked the activity for DRG. The GF extracts protected the SH-SY5Y cells from the neurotoxins 6-OHDA and MPP+, as did NGF and BDNF. This neuroprotective effect of GF was not blocked by anti-NGF Ab. This study suggests that the neurotrophic activity in GF extracts has CNTF-like and BDNF-like components as well as another, undefined component.
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PMID:Traumatized rat striatum produces neurite-promoting and neurotrophic activities in vitro. 865 21

The uptake and cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of the parkinsonism inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were studied in COS-7 cells transiently transfected with the cloned human noradrenaline and dopamine transporters and in permanently transfected SK-N-MC neuroblastoma cells. MPP+ had a 10- to 20-fold lower K(m) value for the noradrenaline than for the dopamine transporter. In dopamine transporter expressing cells, the maximal transport rate (Vmax) of MPP+, dopamine and noradrenaline was the same, but in noradrenaline transporter expressing cells the Vmax of MPP+ and dopamine was only one-half of the Vmax of noradrenaline. The turnover numbers (Vmax of uptake/maximal binding sites of binding) were 5 times higher for the dopamine transporter (as measured with [3H]dopamine and [3H]-2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane than for the noradrenaline transporter (as measured with [3H]noradrenaline and [3H]nisoxetine). In SK-N-MC cells with similar Vmax values for both catecholamines, noradrenaline transporter expressing cells were killed by lower concentrations of MPP+ in the medium than dopamine transporter expressing cells. Desipramine blocked the toxicity of MPP+ toward the noradrenaline transporter, but not the dopamine transporter expressing cells. We conclude that the toxic effect of MPTP at the striatal dopamine system in the MPTP primate model of Parkinson's disease is not correlated with the affinity profile of MPP+ for catecholamine transporters, but rather with the higher turnover number of MPP+ at the dopamine transporter. In contradistinction, the toxicity of MPTP at the noradrenaline neurons in the primate cerebral cortex (Pifl et al., 1991) may involve the higher affinity of MPP+ for the noradrenaline transporter.
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PMID:Catecholamine transporters and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: studies comparing the cloned human noradrenaline and human dopamine transporter. 866 8

A-77636 is a dopamine (DA) D1 receptor-selective agonist that was previously shown to elicit beneficial responses in animal models of Parkinson's disease (PD) (Kebabian et al.: Eur. J. Pharmacol. 229: 203, 1992). However, A-77636 is of limited potential for PD therapy because it induces rapid tolerance in vivo. To understand the basis of rapid onset of tolerance to the compound, we conducted studies to compare the in vitro properties of A-77636 and A-81686; the latter is a structurally related D1 agonist that did not induce significant tolerance in vivo under similar experimental conditions. With SK-N-MC, a neuroblastoma cell line, as an in vitro model for the D1 receptor, significant differences in D1 receptor function were noted after pretreatment with the two compounds. Specifically, 1-hr pretreatment with A-77636 resulted in significant residual cAMP production, even after the drug solution was removed and the cells were washed. The residual cAMP activity was selectively inhibited by SCH 23390, a selective D1 antagonist. The residual cAMP activity declined with pretreatment time, and after 4-hr pretreatment, little residual cAMP production was observed. Cotreatment of SK-N-MC cells with SCH 23390 and A-77636 did not prevent residual cAMP production by A-77636. In contrast, A-81686 did not elicit residual cAMP production is SK-N-MC cells. Although A-77636 treated cells were devoid of agonist response 4 hr after drug removal, A-81686-treated cells exhibited significant cAMP response after drug removal. Preincubation of rat striatal membranes with A-77636 resulted in a large decrease in D1 receptor binding, despite repeated washings, whereas A-81686 pretreatment caused only a small reduction in D1 receptor binding. On the basis of the present data, we conclude that A-77636 dissociates slowly from the D1 receptor. The continued activation of the D1 receptor by A-77636 leads to inability of the receptor to recover its responsivity, which may explain its long duration of action and its ability to induce rapid behavioral tolerance in vivo.
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PMID:Persistent activation of the dopamine D1 receptor contributes to prolonged receptor desensitization: studies with A-77636. 878 31

Rat models of Parkinson's disease typically employ a rapid nigral injection of 6-hydroxydopamine (6-OHDA) to produce a near-complete loss of nigrostriatal dopamine neurons, and thus, model end stage disease. The present report describes the use of a continuous, low dose infusion of 6-OHDA into the striatum which produces a terminal axotomy of nigrostriatal dopamine neurons and protracted behavioral response. A solution of 6-OHDA in 0.4% ascorbate, delivered at 37 degrees C from osmotic minipumps, was stable for 8 days as determined by its retained toxicity to a dopaminergic neuroblastoma cell line. The continuous infusion of 0.2 mu g 6-OHDA per h did not affect the striatal uptake of [3H]%GABA, [3H]choline, or [3H]glutamate but reduced [3H]dopamine uptake by 55% within 1.5 days after the start of the infusion. The striatal infusion of 6-OHDA produced a dose-dependent reduction of striatal dopamine and DOPAC levels but did not alter HVA, 5-HT, or 5-HIAA. An increase in amphetamine-induced ipsiversive rotations occurred within 1.5 days after the acute striatal injection of 20 mu g or 30 mu g of 6-OHDA but required 4 days to develop with the continuous 6-OHDA infusion. The topography of the lesion mapped by [3H]mazindol binding showed that, beginning by 1.5 days, a diffuse depletion of terminals encompassed much of the striatum in the 30 mu g acute injection group, whereas in the continuously infused rats, the lesion was apparent only by 4 days and was restricted to a smaller and more completely lesioned area. Unlike acutely lesioned animals, continuously infused rats revealed no obvious loss of dopamine neurons in the pars compacta by 5 weeks after 6-OHDA. The continuous striatal infusion of 6-OHDA can produce a topographically limited terminal axotomy of dopamine neurons and a protracted behavioral impairment.
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PMID:A continuous striatal infusion of 6-hydroxydopamine produces a terminal axotomy and delayed behavioral effects. 883 64

The mitochondrial electron transport enzyme NADH:ubiquinone oxidoreductase (complex I), which is encoded by both mitochondrial DNA and nuclear DNA, is defective in multiple tissues in persons with Parkinson's disease (PD). The origin of this lesion and its role in the neurodegeneration of PD are unknown. To address these questions, we created an in vitro system in which the potential contributions of environmental toxins, complex I nuclear DNA mutations, and mitochondrial DNA mutations could be systematically analyzed. A clonal line of human neuroblastoma cells containing no mitochondrial DNA was repopulated with mitochondria derived from the platelets of PD or control subjects. After 5 to 6 weeks in culture, these cytoplasmic hybrid (cybrid) cell lines were assayed for electron transport chain activities, production of reactive oxygen species, and sensitivity to induction of apoptotic cell death by 1-methyl-4-phenyl pyridinium (MPP+). In PD cybrids we found a stable 20% decrement in complex I activity, increased oxygen radical production, and increased susceptibility to 1-methyl-4-phenyl pyridinium-induced programmed cell death. The complex I defect in PD appears to be genetic, arising from mitochondrial DNA, and may play an important role in the neurodegeneration of PD by fostering reactive oxygen species production and conferring increased neuronal susceptibility to mitochondrial toxins.
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PMID:Origin and functional consequences of the complex I defect in Parkinson's disease. 887 87

Neurotrophic factors are produced in the striatum following trauma and have a demonstrable effect on in vitro bioassays and on in vivo graft survival. We have previously measured the in vitro effect of these factors following trauma to the striatum of young rats. However, the effect of age on this neurotrophic response has not been evaluated. In this study we report on the in vitro effects of extracts (obtained from gelfoam) removed from striatal cavities 7 days following trauma. Gelfoam extract from aged rats (18-24 months) had a reduced neurite-promoting response in dorsal root ganglia (DRG) and SH-SY5Y (a dopamine-producing neuroblastoma cell line) assays, compared to gelfoam from young rats (2-3 months). In contrast, extracts from both young and old rats showed significant neuroprotection of SH-SY5Y cells from the dopaminergic neurotoxins N-methy-4phenylpyridinium ion (MPP +) and 6-hydroxydopamine (6-OHDA). The results suggest that the striatum of aged individuals may have (1) a diminished capacity of neurite promotion and/ or (2) that neurite outgrowth and neuroprotection may be influenced by different factors or different levels of the same factors. The direct implication is that aged animals would be the most appropriate models to study experimental therapies for Parkinson's disease.
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PMID:In vitro assessment of neurotrophic activity from the striatum of aging rats. 894 52

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

Enhanced oxidative stress has been suggested to be involved in the degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease. The high turnover rate of dopamine and/or unsequestered dopamine may cause an increase of formation of hydrogen peroxide via either oxidative deamination of dopamine by monoamine oxidase or autoxidation. Hydrogen peroxide would be converted to more toxic hydroxyl free radicals. L-beta-3,4-Dihydroxyphenylalanine hydrochloride (L-DOPA), the most useful drug in the symptomatic treatment of Parkinson's disease, has been considered to possess deteriorating degenerative side-effects. The catecholaminergic neuroblastoma SH-SY5Y cells were chosen to investigate the cytotoxic effect of dopamine and L-DOPA. Both dopamine and L-DOPA were found to be cytotoxic towards SH-SY5Y cells. Such toxic effects were accompanied by an increase of oxidative stress in the cell cultures and could be reversed effectively by catalase and to a lesser extent by superoxide dismutase. The non-enzymatic antioxidants L-ascorbic acid, glutathione, N-acetyl-L-cysteine, but not (+)-alpha-tocopherol, also completely protected SH-SY5Y cells against the cytotoxic effects induced by dopamine and L-DOPA. Antioxidative factors, namely free radical scavengers (including N-tert-butyl-alpha-phenylnitrone, salicylic acid, and D-mannitol) and a strong iron chelator, deferoxamine, however, did not protect the SH-SY5Y cells against dopamine and L-DOPA. The generation of reactive oxygen species and the resulting enhanced oxidative stress was clearly involved in the dopamine- and L-DOPA-induced cytotoxic effects. Hydrogen peroxide played the most important role related to cytotoxicity of dopamine and L-DOPA.
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PMID:Dopamine- and L-beta-3,4-dihydroxyphenylalanine hydrochloride (L-Dopa)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells. Effects of oxidative stress and antioxidative factors. 906 40


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