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)

A possible link between Parkinson's disease and pesticide exposure has been suggested, and recently it was shown that the herbicide atrazine (ATR) modulates catecholamine metabolism in PC12 cells and affects basal ganglia function in vivo. Hence, the objectives of this study were to: (i) determine if ATR is capable of modulating dopamine (DA) metabolism in striatal tissue slices in vitro and (ii) explore possible mechanisms of its effects. Striatal tissues from adult male Sprague-Dawley rats were incubated with up to 500 microM ATR in a metabolic shaker bath at 37 degrees C and an atmosphere of 95% O(2) and 5% CO(2) for 4h. At the end of incubation, samples were collected for both tissue and media levels of DA and its metabolites (3,4-dihydroxyphenylacetic acid, DOPAC and homovanillic acid, HVA), which were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). To gain some mechanistic insight in to the way ATR affects DA metabolism, several pharmacological manipulations were performed. Striata exposed to ATR at concentrations of 100 microM and greater had a dose-dependent decrease of tissue levels of DA. At doses of ATR 50 microM and greater, the DOPAC+HVA/DA ratio was dose-dependently increased. Tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) protein levels and activity were not affected by ATR treatment. However, high potassium-induced DA release into the medium was decreased, whereas the increase in media DA observed in the presence of the DA uptake inhibitor nomifensine was increased even further by ATR in a dose-dependent manner. All of these effects of ATR were observed at levels that were not toxic to the tissue, as LDH release into the medium (lactate dehydrogenase, an index of non-specific cytotoxicity) was not affected by ATR. Taken together, results from this study suggest that ATR decreases tissue DA levels not by affecting TH activity, but possibly by interfering with the vesicular storage and/or cellular uptake of DA.
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PMID:Dopaminergic toxicity of the herbicide atrazine in rat striatal slices. 1721 51

Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson's disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. Alpha-synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by (3)H-WIN 35,428 binding and (3)H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD.
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PMID:Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system. 1729

Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD). However, factors mediating microglial activation in PD are poorly understood. Proinflammatory cytokines, such as interferon-gamma (IFN-gamma), orchestrate the actions of microglia. We report here that PD patients express significantly elevated levels of IFN-gamma in their blood plasma. After this initial finding, we found that IFN-gamma-deficient mice displayed attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra pars compacta dopaminergic cell loss along with reduced loss of striatal tyrosine hydroxylase and dopamine transporter fiber density. MPTP-induced depletion of striatal dopamine and its metabolite DOPAC (3,4-dihydroxyphenylacetic acid), as well as deltaFosB, a marker of postsynaptic dysfunction, were also attenuated in these knock-out mice. Consistent with the role for IFN-gamma in microglial activation, MPTP-induced morphological activation of microglia was abrogated compared with wild-type mice. To examine more mechanistically the role of IFN-gamma in microglial activation, we evaluated the interactions between microglia and dopaminergic neurons in an in vitro mixed microglia/midbrain neuron rotenone-induced death paradigm. In this in vitro paradigm, dopaminergic neurons are selectively damaged by rotenone. Exogenous IFN-gamma ligand alone and without rotenone resulted in dopaminergic cell loss, but only in the presence of microglia. The addition of an IFN-gamma neutralizing antibody attenuated neuronal loss as a result of rotenone treatment. The presence of only wild-type microglia and not those deficient in IFN-gamma receptor elicited significant dopaminergic cell loss when exposed to rotenone. Neurons deficient in IFN-gamma receptor, however, did not display increased resistance to death. Finally, levels of IFN-gamma message increased in microglia in response to rotenone. Together, these data suggest that IFN-gamma participates in death of dopaminergic neurons by regulating microglial activity.
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PMID:Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. 1737 93

A single dose of isatin (indole-2,3-dione)(i.p.), an endogenous MAO inhibitor, significantly increased norepinephrine and 5-hydroxytryptamine concentrations in the rat brain and also significantly increased acetylcholine and dopamine (DA) levels in the rat striatum. Urinary isatin concentrations in patients with Parkinson's disease tend to increase according to the severity of disease. We have developed a rat model of Parkinson's disease induced by the Japanese encephalitis virus (JEV). The distribution of the pathological lesions of JEV-rats resemble those found in Parkinson's disease. Significant behavioral improvement was observed in JEV-rats after isatin, L-DOPA and selegiline administration using a pole test. Both isatin and selegiline prevented the decrease in striatum DA levels of JEV-rats. The increased turnover of DA (DOPAC/DA) induced by JEV was significantly inhibited by isatin, but not selegiline. These findings suggest that JEV-infected rats may serve as a model of Parkinson's disease and that exogenously administered isatin and selegiline can improve JEV-induced parkinsonism by increasing DA concentrations in the striatum.
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PMID:Isatin, an endogenous MAO inhibitor, and a rat model of Parkinson's disease induced by the Japanese encephalitis virus. 1744 19

Paraquat is a toxin suggested to contribute to pathogenesis of Parkinson's disease. The aim of the present study was to examine toxic influence of subchronic treatment with this pesticide (5 days, one injection per day, 2-3 days of withdrawal) on dopaminergic, serotonergic, noradrenergic and GABAergic neurons. Paraquat decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra by 22% (measured 3 days after withdrawal). Two days after withdrawal the levels of the dopamine metabolites and dopamine turnover in the caudate-putamen, substantia nigra and prefrontal cortex were reduced by ca. 20-60%, and the binding of [(3)H]GBR 12,935 to dopamine transporter dropped by 25-40% in the caudate-putamen. Three days after paraquat withdrawal, the level of dopamine in the caudate-putamen was significantly increased, and earlier decreases in DOPAC and HVA in the substantia nigra, as well as [(3)H]GBR 12,935 binding in the caudate-putamen were reversed. Moreover, an increase in serotonin turnover in the caudate-putamen and prefrontal cortex, and noradrenaline level in the former structure was observed 2-3 days after paraquat withdrawal. Three days after the last paraquat injection 24-35% decreases in the proenkephalin mRNA levels and 5-7% reduction in glutamic acid decarboxylase (GAD)67 mRNA were found in the caudate-putamen. The present study suggests that subchronic paraquat administration triggers processes characteristic of early stages of dopaminergic neuron degeneration, and activates compensatory mechanisms involving dopaminergic, noradrenergic, serotonergic and GABAergic transmissions.
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PMID:Toxic influence of subchronic paraquat administration on dopaminergic neurons in rats. 1749 92

The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is responsible for packaging dopamine into vesicles for subsequent release and has been suggested to serve a neuroprotective role in the dopamine system. Here, we show that mice that express approximately 5% of normal VMAT2 (VMAT2 LO) display age-associated nigrostriatal dopamine dysfunction that ultimately results in neurodegeneration. Elevated cysteinyl adducts to L-DOPA and DOPAC are seen early and are followed by increased striatal protein carbonyl and 3-nitrotyrosine formation. These changes were associated with decreased striatal dopamine and decreased expression of the dopamine transporter and tyrosine hydroxylase. Furthermore, we observed an increase in alpha-synuclein immunoreactivity and accumulation and neurodegeneration in the substantia nigra pars compacta in aged VMAT2 LO mice. Thus, VMAT2 LO animals display nigrostriatal degeneration that begins in the terminal fields and progresses to eventual loss of the cell bodies, alpha-synuclein accumulation, and an L-DOPA responsive behavioral deficit, replicating many of the key aspects of Parkinson's disease. These data suggest that mishandling of dopamine via reduced VMAT2 expression is, in and of itself, sufficient to cause dopamine-mediated toxicity and neurodegeneration in the nigrostriatal dopamine system. In addition, the altered dopamine homeostasis resulting from reduced VMAT2 function may be conducive to pathogenic mechanisms induced by genetic or environmental factors thought to be involved in Parkinson's disease.
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PMID:Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. 1765 4

Long-term treatment of L-dopa for Parkinson's disease (PD) patients induces adverse effects, including dyskinesia, on-off and wearing-off symptoms. However, the cause of these side effects has not been established to date. In the present study, therefore, 3-O-methyldopa (3-OMD), which is a major metabolite of L-dopa, was tested to determine whether it plays a role in the aforementioned adverse effects. The effects of 3-OMD on the dopaminergic nervous system in the brain were investigated, by examining behavioral, biochemical, and cellular changes in male Sprague-Dawley rats and catecholamine-producing PC12 neuronal cells. The results revealed that the intracerebroventricular (icv) injection of 1 micromol of 3-OMD impaired locomotor activities by decreasing movement time (MT), total distance (TD), and the number of movement (NM) by 70, 74 and 61%, respectively. The biochemical analysis results showed that a single administration of 1 micromole of 3-OMD decreased the dopamine turnover rate (DOPAC/DA) by 40.0% in the rat striatum. 3-OMD inhibited dopamine transporter and uptake in rat brain striatal membranes and PC12 cells. The subacute administration of 3-OMD (5 days, icv) also significantly impaired the locomotor activities and catecholamine levels. 3-OMD induced cytotoxic effects via oxidative stress and decreased mitochondrial membrane potential in PC12 cells, indicating that 3-OMD can damage neuronal cells. Furthermore, 3-OMD potentiated L-dopa toxicity and these toxic effects induced by both 3-OMD and L-dopa were blocked by vitamin E (alpha-tocopherol) in PC12 cells, indicating that 3-OMD may increase the toxic effects of L-dopa to some extent by oxidative stress. Therefore, the present study reveals that 3-OMD accumulation from long-term L-dopa treatment may be involved in the adverse effects of L-dopa therapy. Moreover, L-dopa treatment might accelerate the progression of PD, at least in part, by 3-OMD.
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PMID:The role of 3-O-methyldopa in the side effects of L-dopa. 1771 53

Transplantation of neural stem cells (NSC) derived dopamine (DA) neurons has emerged as an alternative approach to fetal neural cell transplantation in Parkinson's disease (PD). However, similar to fetal neural cell, survival of these neurons following transplantation is also limited due to limited striatal reinnervation (graft with dense neuronal core), limited host-graft interaction, poor axonal outgrowth, lack of continuous neurotrophic factors supply and principally an absence of cell adhesion molecules mediated appropriate developmental cues. In the present study, an attempt has been made to increase survival and function of NSC derived DA neurons, by co-grafting with Zuckerkandl's organ (a paraneural organ that expresses neurotrophic factors as well as cell adhesion molecules); to provide continuous NTF support and developmental cues to transplanted DA neurons in the rat model of PD. 24 weeks post transplantation, a significant number of surviving functional NSC derived DA neurons were observed in the co-transplanted group as evident by an increase in the number of tyrosine hydroxylase immunoreactive (TH-IR) neurons, TH-IR fiber density, TH-mRNA expression and TH-protein level at the transplantation site (striatum). Significant behavioral recovery (amphetamine induced stereotypy and locomotor activity) and neurochemical recovery (DA-D2 receptor binding and DA and DOPAC levels at the transplant site) were also observed in the NSC+ZKO co-transplanted group as compared to the NSC or ZKO alone transplanted group. In vivo results were further substantiated by in vitro studies, which suggest that ZKO increases the NSC derived DA neuronal survival, differentiation, DA release and neurite outgrowth as well as protects against 6-OHDA toxicity in co-culture condition. The present study suggests that long-term and continuous NTF support provided by ZKO to the transplanted NSC derived DA neurons, helped in their better survival, axonal arborization and integration with host cells, leading to long-term functional restoration in the rat model of PD.
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PMID:Zuckerkandl's organ improves long-term survival and function of neural stem cell derived dopaminergic neurons in Parkinsonian rats. 1827 52

We investigated the effects of the polyphenolic compound curcumin and its metabolite tetrahydrocurcumin (ThC), in the model of Parkinson's disease induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this model depletion of dopamine(DA) and DOPAC (3,4-dihydroxy phenyl acetic acid)) occurs with increased monoamine oxidase (MAO-B) activity. We used HPLC with electrochemical detection to measure DA and DOPAC respectively while MAO-B was assayed by spectroflourimetry using the conversion of the fluorogenic substrate, kyuramine. Systemic administration of curcumin (80 mg/kg i. p.) and tetrahydrocurcumin (60 mg/kg i. p.) significantly reversed the MPTP-induced depletion of DA and DOPAC. The MAO-B activity was also significantly inhibited by these compounds. The results showed that curcumin and tetrahydrocurcumin reversed the MPTP induced depletion of DA and DOPAC which may in part be due to inhibition of MAO-B activity. In conclusion, both curcumin and its metabolite ThC exert neuroprotection against MPTP induced neurotoxicity.
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PMID:Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson's disease induced by MPTP neurodegeneration in mice. 1840 3

To explore a recently established association between histaminergic and dopaminergic neuronal phenotypic systems in brain, we determined the effect of the respective histaminergic H(3) receptor agonist and antagonist/inverse agonist, imetit and thioperamide, on L-DOPA - derived tissue and extracellular DA and metabolite levels in the striatum of 6-hydroxydopamine (6-OHDA) - lesioned rats (i.e., parkinsonian rats). We also examined the influence of histamine H(3) ligands on L-DOPA evoked behavioral responses (locomotor activity, number of rearings, stereotyped behavior and motor coordination). Using HPLC/ED and in vivo microdialysis technique imetit (5 mg/kg, i.p.) but not thioperamide (5 mg/kg, i.p.) was shown to attenuate an L-DOPA-evoked (15 mg/kg, i.p.; carbidopa, 30 min pretreatment) increase in extracellular DA in the neostriatum of 6-OHDA-lesioned rats. However, both imetit and thioperamide increased microdialysate levels of DOPAC and HVA, probably by enhancing intraneuronal DA utilization. As indicated by neurochemical analysis of the striatum imetit produced a decrease in tissue DA content. These findings support the hypothesis that central H(3) histaminergic receptors have a modulatory role in the storage, metabolism and release of DA derived from exogenous L-DOPA challenge. Furthermore, evidence from behavioral studies indicate that histamine H3 receptor blockade markedly improved motor coordination. Conversely, histamine H(3) receptor stimulation, being without effect on motor coordination, enhanced vertical activity in rats. From the above we conclude that the histamine H(3) agonism may augment motor dyskinesia in Parkinson's disease (PD) patients and presumably worsen L-DOPA therapy. Consequently, the histaminergic system represents a viable target for modulating the effectiveness of L-DOPA therapy in Parkinson's disease.
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PMID:Histamine H(3) receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa derived extracellular dopamine in dopamine-denervated rat striatum. 1852 2


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