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)

Dopaminergic cell loss in the mesencephalic substantia nigra is the hallmark of Parkinson's disease and may be associated with abnormal oxidative metabolic activity. However, the delicate balance underlying dopamine decline and oxidative stress is still a matter of debate. The aim of this study was to analyze the possible modulation of D2 agonists and antagonists on MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion) -induced cellular death in differentiated and undifferentiated PC12 cells. Using colorimetric assays, western blots and reverse transcriptase-PCR, we demonstrated that two D2 agonists, bromocriptine and quinpirole, consistently increased MPP+ -induced cytotoxicity in both differentiated and undifferentiated PC12 cells, whereas D2 antagonists do not modulate cell death. However, this increase in cellular death was reversed when bromocriptine or quinpirole were used in presence of D2 antagonists. On the other hand, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909), a potent inhibitor of the dopamine transporter, partially reversed MPP+ -induced cellular death and completely abolished the increase of cellular death induced by bromocriptine. Dopamine agonists and antagonists also modulate the expression of the dopamine transporter in PC12 cells; in particular, bromocriptine may alter MPP+ uptake by increasing DAT expression We also show that, in our cellular paradigm, D2 receptor mRNA levels are more abundant that D3 mRNA levels and MPP+ and /or bromocriptine could not modulate D2 gene expression while D3 gene expression clearly decrease after MPP+ and /or bromocriptine treatment.
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PMID:Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+ -induced toxicity in PC12 cells. 1700 Apr 68

Camptocormia is characterised as an extreme bent-forward posture of the trunk that disappears in the recumbent position. On X-ray, trunk flexion appears without vertebral rotation as in scoliosis. The condition is a well-known complication of Parkinson's disease (PD) at the late stage. The authors present the case of a 77-year-old woman affected by severe camptocormia, which appeared and worsened in less than 6 months and hindered gait. Despite no signs of PD, neuro-imaging (DAT-Scan) showed an L-Dopa transducer decrease in putamens. A few weeks later, bradykinesia appeared and the clinical diagnosis of PD became more obvious. L-Dopa improved bradykinesia but did not change the bent-spine posture. A 1-year follow-up showed no other signs of PD other than bradykinesia, but the camptocormia was unchanged.
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PMID:[Camptocormia disclosing Parkinson's disease]. 1702 15

We describe the development of a novel animal model of acute severe dopamine (DA) deficiency by using genetically altered mice lacking the DA transporter (DAT-KO mice). In the absence of a DAT-mediated recycling mechanism in these mice, striatal DA concentrations become entirely dependent on its de novo synthesis, and acute pharmacologic inhibition of tyrosine hydroxylase induces transient (up to 16 hours) elimination of brain DA. Dopamine-deficient DAT-KO mice (DDD mice) demonstrate a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. We propose that DDD mice represent a novel acute model of severe DA deficiency that might be used to identify compounds with potential therapeutic use for the treatment of Parkinson's disease (PD). This model is particularly promising as a tool for evaluating the efficacy of compounds that may induce movement independently of DA. The advantages and limitations of DDD mice in comparison to other rodent PD models are discussed.
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PMID:DDD mice, a novel acute mouse model of Parkinson's disease. 1703 Jul 35

The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)) and depression has long been recognized. However, many of these important findings have resulted from studies in vitro using postmortem tissues; as of now, these results have never been verified via in vivo methods because brain imaging of NET in living systems has been hampered due to the lack of suitable radioligands. The fact that all three monoamine (dopamine, norepinephrine, and serotonin) transporters (DAT, NET and SERT) are involved in various neurological and psychiatric diseases further emphasizes the need to develop suitable NET ligands so that researchers will be able to probe the contributions of each monoamine transporter system to specific CNS disorders. In this review article, the design and biological evaluation of several radioligands for imaging the brain NET system with PET are discussed. Based on these characterization studies, including C-11 labeled desipramine (DMI), 2-hydroxydesipramine (HDMI), talopram, talsupram, nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and C-11 and F-18 derivatives of reboxetine (RB), methylreboxetine (MRB) and their individual (R, R) and (S, S) enantiomers, in conjunction with studies with radiolabeled 4-iodo-tomoxetine and 2-iodo-nisoxetine, we have identified the superiority of (S, S)-[(11)C]MRB and the suitability of the MRB analogs as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge, (S, S)-[(11)C]MRB remains by far the most promising NET ligand for PET studies.
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PMID:PET imaging of norepinephrine transporters. 1707 82

We used qualitative visual assessment and semiquantitative measures of striatal DAT binding using [(123)I]FP-CIT-SPET in 85 patients with Parkinson's disease (PD). We compared these two assessments and their correlation with PD clinical progression. SPET imaging was visually classified by a nuclear medicine physician as normal or abnormal pattern grade I, II and III, in relation to a different degree of radioligand reduction uptake. Nineteen patients presented abnormal grade I (group 1), 53 grade II (group 2) and 13 grade III (group 3). The UPDRS III motor score, the H-Y score, the rigidity and bradykinesia subscores were significantly different among the three groups. Post hoc analysis showed that all values of these clinical parameters were higher in group 3 than in 2 and 1. All clinical indices were also significantly higher in group 2 than in group 1. This means that groups 3 and 2 were clinically more severely affected. No significant differences among the 3 groups were observed for age or duration of disease. Values of the mean striatum uptake were also significantly different among the three groups. Post hoc analysis revealed significantly lower values of the mean striatum uptake in group 3 with respect to groups 2 and 1; values were also significantly lower in group 2 than in group 1. We conclude that our findings of good consistency between visual and semi-quantitative assessment may help simplify the evaluation of striatal DAT binding in PD in a clinical routine setting.
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PMID:Comparative analysis of visual and semi-quantitative assessment of striatal [123I]FP-CIT-SPET binding in Parkinson's disease. 1720 24

The striatum -- the largest integrative component of the basal ganglia -- harbors a population of neurons that express the enzyme tyrosine hydroxylase (TH), a faithful marker of dopaminergic neurons. The dopaminergic nature of these neurons is further supported by the fact that they express the dopamine (DA) transporter (DAT) and the nuclear orphan receptor Nurr1, a transcription factor essential for the expression of the DA phenotype by midbrain neurons. The vast majority of these neurons are morphologically similar to the medium-sized aspiny striatal interneurons and they all express the enzyme GAD(65). The striatal TH-positive neurons increase markedly in number in animal models of Parkinson's disease (PD), where striatal DA concentrations are low, but this increase is abolished by L-dopa treatment. Hence, local DA concentrations appear to regulate the numerical density of this ectopic neuronal population, a phenomenon that is more likely the result of a shift in the phenotype of preexistent striatal interneurons rather than the recruitment of newborn neurons that will develop a DA phenotype. Altogether, these findings suggest that striatal TH-positive neurons act as a local source of DA and, as such, are part of a compensatory mechanism that could be artificially enhanced to alleviate or delay PD symptoms.
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PMID:Dopaminergic neurons intrinsic to the striatum. 1728 88

Neuronal monoamine transporters (MATs) are involved in the pathophysiology and treatment of mental health conditions such as depression, attention deficit hyperactivity disorder, substance abuse and neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. Various structural classes of compounds have been synthesized and tested in vitro for activity against transporters of three monoamine signaling molecules: noradrenaline (NET); serotonin (SERT) and dopamine (DAT). We have developed and validated a number of pharmacophore models describing the interaction of two classes of compounds with each of these three MATs. These pharmacophores explain the selectivity of binding to the MATs for various compound classes and have been used to search in silico databases for novel, potentially selective ligands. These ligands, after confirmation of their activities, will provide tools for investigating the function of MATs as well as the potential for new therapeutic agents in mental health applications. The database searches also retrieved close analogues of known MAT ligands, further validating the approach.
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PMID:Pharmacophore design and database searching for selective monoamine neurotransmitter transporter ligands. 1802 78

There is growing evidence indicating that reactive nitrogen species (RNS) and reactive oxygen species (ROS) are a major contributor to the pathogenesis and progression of Parkinson's disease. Here we investigated whether edaravone (free radical scavenger), minocycline (inducible nitric oxide synthase, iNOS inhibitor), 7-nitroindazole (neuronal NOS, nNOS inhibitor), fluvastatin (endothelial NOS, eNOS activator) and pitavastatin (eNOS activator) can protect against MPTP neurotoxicity in mice under the same condition. The present study showed that 7-nitroindazole could protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletion. Our immunohistochemical study showed that TH (tyrosine hydroxylase) and DAT (dopamine transporter) immunoreactivity was decreased significantly in the striatum and substantia nigra 5 days after MPTP treatment. The administration of 7-nitroindazole showed a protective effect against the severe reductions in levels of TH and DAT immunoreactivity in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the remarkable loss of TH protein levels in the striatum 5 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant loss in TH protein levels in the striatum 5 days after MPTP treatment. On the other hand, GFAP (glial fibrillary acidic protein) immunoreactivity increased significantly in the striatum and substantia nigra, 5 days after MPTP treatment. 7-Nitroindazole ameliorated severe increases in number of GFAP immunoreactive astrocytes in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the increase of GFAP protein levels in the striatum 5 days after MPTP treatment. 7-Nitroindazole prevented a significant increase in the GFAP protein levels in the striatum 5 days after MPTP treatment. The present results indicate that 7-nitroindazole can protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletions. These findings demonstrate that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared to the production of ROS, the overexpression of iNOS and the modulation of eNOS. Thus, our findings provide strong evidence for neuroprotective properties of nNOS inhibitor in this animal model of Parkinson's disease.
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PMID:Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice. 1823 88

Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. The performance of animal studies allows the induction of specific short-term or long-term synaptic conditions via pharmacological challenges or infliction of neurotoxic lesions. Therefore, small laboratory animals such as rats and mice have become invaluable models for a variety of human disorders. This article gives an overview of those small animal studies which have been performed so far on dopaminergic neurotransmission using in vivo imaging methods, with a special focus on the relevance of findings within the functional entity of the dopaminergic synapse. Taken together, in vivo investigations on animal models of Parkinson's disease showed decreases of dopamine storage, dopamine release and dopamine transporter binding, no alterations of dopamine synthesis and DA release, and either increases or no alterations of D2 receptor binding, while in vivo investigations of animal models of Huntington's disease. showed decreases of DAT and D1 receptor binding. For D2 receptor binding, both decreases and increases have been reported, dependent on the radioligand employed. Substances of abuse, such as alcohol, amphetamine and methylphenidate, led to an increase of dopamine release in striatal regions. This held for the acute application of substances to both healthy animals and animal models of drug abuse. Findings also showed that chronic application of cocaine induced long-term reductions of both D1 and D2 receptor binding, which disappeared after several weeks of withdrawal. Finally, preliminary results yielded the first evidence that acute pplication of haloperidol might induce a reduction of dopamine transporter binding, indicating an enhancement of dopamine release into the synaptic cleft. It is remarkable to what degree the findings obtained with small animal imaging devices correspond to the results of clinical and experimental studies on humans. This agreement underlines the validity of small animal imaging methods and demonstrates the feasibility of further investigations on animal models of human diseases.
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PMID:Investigating the dopaminergic synapse in vivo. II. Molecular imaging studies in small laboratory animals. 1833 Feb 13

Association between multiple sclerosis (MS) and parkinsonism is rarely reported. We describe clinical, radiological and DAT scan findings in two patients presenting with parkinsonism. MRI revealed demyelinating lesions of the central nervous system consistent with MS in both patients. On the other hand, DAT scan findings were supportive of Parkinson's disease. There is still an open debate whether MS lesions can cause parkinsonism, or these are just coincidental findings of two different diseases in the same patient. Although there are cases of causal relationship between parkinsonism and MS, some literature reports and our observations suggest that Parkinson's disease and MS can coexist as two separate diseases in the same patient. It is possible that the symptoms of Parkinson's disease can be aggravated by MS plaques, explaining the favorable response to corticosteroids in some patients.
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PMID:Parkinsonism and multiple sclerosis--is there association? 1848 94


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