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)

1-Methyl-4-phenylpyridinium (MPP+) is a mitochondrial Complex I inhibitor and is frequently used to investigate the pathological degeneration of neurons associated with Parkinson's disease (PD). In vitro, extracellular concentration of glucose is one of the most critical factors in establishing the vulnerability of neurons to MPP+ toxicity. While glucose is the primary energy fuel for the brain, central nervous system (CNS) neurons can also take up and utilize other metabolic intermediates for energy. In this study, we compared various monosaccharides, disaccharides, nutritive/non-nutritive sugar alcohols, glycolytic and gluconeogenic metabolic intermediates for their cytoprotection against MPP+ in murine brain neuroblastoma cells. Several monosaccharides were effective against MMP+ (500 microM) including glucose, fructose and mannose, which restored cell viability to 109 +/- 5%, 70 +/- 5%, 99 +/- 3% of live controls, respectively. Slight protective effects were observed in the presence of 3-phosphoglyceric acid and glucose-6-phosphate; however, no protective effects were exhibited by galactose, sucrose, sorbitol, mannitol, glycerol or various gluconeogenic and ketogenic amino acids. On the other hand, fructose 1,6 bisphosphate and gluconeogenic energy intermediates [pyruvic acid, malic acid and phospho(enol)pyruvate (PEP)] were neuroprotective against MPP+. The gluconeogenic intermediates elevated intracellular levels of ATP and reduced propidium iodide (PI) nucleic acid staining to live controls, but did not alter the MPP(+)-induced loss of mitochondrial O2 consumption. These data indicate that malic acid, pyruvic acid and PEP contribute to anaerobic substrate level phosphorylation. The use of hydrazine sulfate to impede gluconeogenesis through PEP carboxykinase (PEPCK) inhibition heightened the protective effects of energy substrates possibly due to attenuated ATP demands from pyruvate carboxylase (PC) activity and pyruvate mitochondrial transport. It was concluded from these studies that several metabolic intermediates are effective in fueling anaerobic glycolysis during mitochondrial inhibition by MPP+.
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PMID:The role of glycolysis and gluconeogenesis in the cytoprotection of neuroblastoma cells against 1-methyl 4-phenylpyridinium ion toxicity. 1256 89

Complex-I inhibition and oxidative processes have been implicated in the loss of nigral dopamine neurones in Parkinson's disease and the toxicity of MPTP and its metabolite MPP+. Tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase, may act as an antioxidant in dopaminergic neurones and protects against the toxic consequences of glutathione depletion. Here we studied the effects of manipulating tetrahydrobiopterin levels on MPP+ toxicity in organotypic, rat ventral mesencephalic slice cultures. In cultures exposed to 30 micro m MPP+ for 2 days, followed by 8 days 'recovery' in control medium, we measured dopamine and its metabolites in the tissue and culture medium by HPLC, lactate dehydrogenase release to the culture medium, cellular uptake of propidium iodide and counted the tyrosine hydroxylase-immunoreactive neurones. Inhibition of tetrahydrobiopterin synthesis by 2,4-diamino-6-hydroxypyrimidine had no significant synergistic effect on MPP+ toxicity. In contrast, the tetrahydrobiopterin precursor l-sepiapterin attenuated the MPP+-induced dopamine depletion and loss of tyrosine hydroxylase-positive cells in a dose-dependent manner with 40 micro m l-sepiapterin providing maximal protection. Accordingly, increasing intracellular tetrahydrobiopterin levels may protect against oxidative stress by complex-I inhibition.
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PMID:Tetrahydrobiopterin precursor sepiapterin provides protection against neurotoxicity of 1-methyl-4-phenylpyridinium in nigral slice cultures. 1264 43

We have established stable transfectants expressing beta-synuclein in TSM1 neurons. We show that in basal and staurosporine-induced conditions the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL)-positive beta-synuclein-expressing neurons was drastically lower than in mock-transfected TSM1 cells. This was accompanied by a lower DNA fragmentation as evidenced by the reduction of propidium iodide incorporation measured by fluorescence-activated cell sorter analysis. beta-Synuclein strongly reduces staurosporine-induced caspase 3 activity and immunoreactivity. We establish that beta-synuclein triggers a drastic reduction of p53 expression and transcriptional activity. This was accompanied by increased Mdm2 immunoreactivity while p38 expression appeared enhanced, indicating that beta-synuclein-induced p53 down-regulation likely occurs at a post-transcriptional level. We showed previously that alpha-synuclein displays an antiapoptotic function that was abolished by the dopaminergic derived toxin 6-hydroxydopamine (6OHDA). Interestingly, beta-synuclein retains its ability to protect TSM1 neurons even after 6OHDA treatment. Furthermore, beta-synuclein restores the antiapoptotic function of alpha-synuclein in 6OHDA-treated neurons. Altogether, our data document for the first time that beta-synuclein protects neurons from staurosporine and 6OHDA-stimulated caspase activation in a p53-dependent manner. Our observation that beta-synuclein contributes to restoration of the alpha-synuclein antiapoptotic function abolished by 6OHDA may have direct implications for Parkinson's disease pathology. In this context, the cross-talk between these two parent proteins is discussed.
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PMID:Beta-synuclein displays an antiapoptotic p53-dependent phenotype and protects neurons from 6-hydroxydopamine-induced caspase 3 activation: cross-talk with alpha-synuclein and implication for Parkinson's disease. 1286 15

Presymptomatic diagnosis of the loss of nigrostriatal neurons that characterises Parkinson's disease, is a crucial issue for future neuroprotective therapies as degeneration exceeds 70 to 80% when symptoms appear. Here we propose an early diagnosis method that utilises single photon emission computerized tomography (SPECT) coupled to the iodine-123-labelled selective dopamine transporter ligand N-(3-ioprop-2E-enyl)-2-beta-(4-methylphenyl)nortropane ((123)I-PE2I), applying Logan's graphical method for quantification. Sequential (123)I-PE2I SPECT acquisitions were performed in nonhuman primates chronically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that consistently produces a progressive Parkinsonian state. While classical neurological examination only allows detection of Parkinsonian signs at Day 12 of the protocol of intoxication, the mean distribution volume ratio calculated according to Logan's graphical method is significantly decreased from Day 6 onward, i.e., when animals are clinically normal. (123)I-PE2I SPECT is a very sensitive method to detect presymptomatic lesions of nigrostriatal neurons and the first to be experimentally validated. It could now be used clinically for early diagnosis and follow-up of neuroprotective treatment.
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PMID:Presymptomatic diagnosis of experimental Parkinsonism with 123I-PE2I SPECT. 1288 Aug 9

A 66-year-old man developed a fever and had a syncopal attack during treatment with imipramine and amantadine for depression and Parkinson's disease. His muscular enzyme levels were very high, so he was diagnosed with incomplete syndrome malin and given hydration therapy. The electrocardiogram recorded an ST segment elevation like acute myocardial infarction in most leads, and the echocardiogram revealed left ventricular dysfunction with severe hypokinesis to dyskinesis of the anterior and apical wall regions, and hyperkinesis of the basal wall. One month from onset, the left ventricular contractility had not changed despite normal coronary arteries. Thallium-201((201)Tl) myocardial scintigraphy showed a perfusion defect and there was no accumulation of iodine-123((123)I) metaiodobenzylguanidine (MIBG) in the entire apex of the heart. Left ventricular function returned to normal and repeat (201)Tl scintigraphy showed recovery by the 4th month. However, there was still an absence of cardiac MIBG uptake. There are a number of reports from Japan of a syndrome demonstrating such reversible left ventricular dysfunction, called 'tako-tsubo cardiomyopathy', but the present case is the first to be associated with syndrome malin. A coronary microvascular abnormality and cardiac sympathetic denervation probably both play an important role in tako-tsubo cardiomyopathy.
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PMID:'Tako-Tsubo cardiomyopathy' associated with syndrome malin: reversible left ventricular dysfunction. 1289 Sep 19

Iometopane [(123)I beta-CIT, GPI 200, RTI 55], a tropane derivative labelled with iodine-123, is a dopamine imaging agent that was under development with Guilford Pharmaceuticals (as Dopascan Injection) for the early diagnosis of Parkinson's disease. Neurochemical imaging with iometopane using conventional single photon emission computerised tomography (SPECT) provided images of the brain for the distinguished diagnosis of Parkinson's disease. The ability of iometopane to bind to the dopamine transporter on presynaptic dopaminergic nerve terminal in the striatum (caudate nucleus and putamen) has been used to differentiate the uptake of the agent by the neurons in the striatum in patients with a Parkinsonian disorder (Parkinson's disease and progressive supranuclear palsy) from patients without a Parkinsonian disorder (essential tremor and healthy controls) with high sensitivity and specificity. The diminished uptake of iometopane in the striatum on the SPECT images of patients with a Parkinsonian disorder can be applied to assess both disease trait and disease state (severity) reflected by the severity of the brain dopamine neuron loss. The rate of clinical progression of Parkinson's disease varies greatly and is currently unpredictable. Imaging with iometopane provides the opportunity to evaluate patients longitudinally from early to late disease using an objective biomarker for dopamine nerve cell degeneration. Diagnostic imaging with Dopascan Injection is thought to differentiate Parkinson's disease from other forms of tremor, eliminate tests such as MRI and CT scans, unnecessary and inappropriate medications (psychotropics), and significantly reduce the number of people remaining on Parkinson's disease medications for life, despite not having Parkinson's disease. Guilford Pharmaceuticals acquired the licence for iometopane from the Research Triangle Institute, US, and sub-licensed it to Daiichi Radioisotope Laboratories for marketing, sales and distribution in Japan, Korea and Taiwan. In July 2003, Daiichi Radioisotope Laboratories paid a milestone payment of $0.55 million to Guilford after filing an application for approval in Japan. In January 2002, Guilford signed an exclusive European development, marketing and sales and distribution agreement for iometopane with MAP Medical Technologies of Finland. Under the terms of the agreement, MAP Medical Technologies will assume responsibility for regulatory approvals, manufacturing, marketing and selling the agent in all member states of the EU and other selected markets. In return, Guilford will receive an upfront payment, milestone payments and royalties on future sales in these territories. In July 2002, MAP Medical Technologies become a subsidiary of Schering AG. In March 2002, Guilford Pharmaceuticals sublicensed iometopane to Molecular Neuroimaging LLC (MNI) of Connecticut, USA. Under the terms of the agreement, MNI will pay a royalty for each administration of iometopane, and also provide Guilford Pharmaceuticals with favourable pricing for the services (including administration of iometopane) for any clinical trials of Guilford's product candidates. This agreement will be terminated upon the US FDA's approval of the product candidate for marketing and sale in the US. Guilford has retained commercial rights to Dopascan Injection in the US. MAP Medical Technologies (Schering AG) submitted a Marketing Authorisation Application (MAA) in Finland for European approval of iometopane for the diagnosis of Parkinson's disease in April 2002. Daiichi Radioisotope Laboratories filed an application for approval of iometopane (Dopascan Injection) for the diagnosis of Parkinson's disease in Japan in July 2003. Guilford Pharmaceuticals is conducting a phase II clinical trial in 200 patients with Parkinson's disease where iometopane imaging is used to assess the effectiveness of GPI 1485, an investigational drug candidate, at baseline and at one year and two years after treatment with either GPI 1485 or placebo. The enrolment is expected to be completed in Q3 of 2003. Guint with either GPI 1485 or placebo. The enrolment is expected to be completed in Q3 of 2003. Guilford Pharmaceuticals decided not to proceed with phase III clinical trials and further development of iometopane due to its inability to contract a suitable manufacturer for the clinical and commercial supply of iometopane on acceptable conditions in the US. Guilford Pharmaceuticals obtained the patent coverage for iometopane in the US, Australia and Europe (Austria, Belgium, Switzerland, Liechtenstein, Germany, Denmark, Spain, France, the United Kingdom, Italy, Luxembourg, the Netherlands, Sweden and Greece). Separate filings were made in Finland, Norway, Japan, Canada and Korea. The manufacturing methods of Dopascan are protected by patents in the US and Europe. Dopascan is a registered trademark in the US, Canada, Europe and Asia.
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PMID:Iometopane: (123)I beta-CIT, dopascan injection, GPI 200, RTI 55. 1295 3

Dopamine receptor agonists are protective in different models of neurodegeneration by both receptor-dependent and -independent mechanisms. We used SH-SY5Y cells, differentiated into neuron-like type, to evaluate if cabergoline, a dopamine D2 receptor agonist endowed with anti-oxidant activity, protects the cells against ischemia (oxygen-glucose deprivation model). Cabergoline protected the cells from ischemia-induced cell death in a concentration-dependent manner (EC(50)=1.2 microM), as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release, and fluorescein diacetate-propidium iodide staining. This effect, observed even when the drug was added after oxygen-glucose deprivation, was not mediated by either dopamine D2 receptor activation or anti-apoptotic Bcl-2 protein over-expression (Western blotting analysis), but was linked to a reduction in cellular free radical loading (2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining) and membrane lipid peroxidation (thiobarbituric acid-reacting test). In conclusion, cabergoline protects in vitro neurons against ischemia-induced cell death, suggesting its possible use in the therapy of other neurodegenerative diseases in addition to Parkinson's disease.
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PMID:Cabergoline protects SH-SY5Y neuronal cells in an in vitro model of ischemia. 1508 38

Methods provided by nuclear medicine may be helpful in diagnosis of Parkinson's disease (PD). For that purpose, the sensitivity of iodine-123 metaiodobenzylguanidine ([123I]MIBG) scintigraphy and [123I]FP-CIT single photon emission computed tomography (SPECT) was studied in patients with PD onset (Hoehn and Yahr Stage 1). Cerebral [123I]FP-CIT and cardiac [123I]MIBG scintigraphy were carried out in 18 patients with idiopathic Parkinson's disease, according to Hoehn and Yahr Stage 1. For quantification purposes, we calculated the striatum/posterior lobe binding of FP-CIT and the heart-to-mediastinum (H/M) count ratio regarding MIBG scintigraphy. In 15 of 18 patients, we observed markedly reduced or asymmetric striatal FP-CIT tracer accumulation. FP-CIT binding of the affected striatum was significantly lower as compared with that of the unaffected side. Striatal FP-CIT binding correlated significantly with the motor part of the Unified Parkinson's disease rating scale (UPDRS) but not with age, disease duration, or gender. MIBG scintigraphy delivered significant pathological results in 13 of 18 patients. There was no significant correlation between the H/M ratio relating to MIBG scintigraphy and the motor part of UPDRS, age, disease duration, or gender; however, binding of striatal FP-CIT correlated significantly with cardiac MIBG accumulation. According to the clinical criteria, it might be difficult to prove the diagnosis of PD in patients with slight symptoms and in these cases, FP-CIT SPECT and MIBG scintigraphy may contribute to the early diagnosis of PD. In addition, the functional loss of nigrostriatal and cardiac sympathetic neurons seems to be coupled closely.
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PMID:FP-CIT and MIBG scintigraphy in early Parkinson's disease. 1564 31

In case of injury or disease, microglia are recruited to the site of the pathology and become activated as evidenced by morphological changes and expression of pro-inflammatory cytokines. Evidence suggests that microglia proliferate by cell division to create gliosis at the site of pathological conditions such as the amyloid plaques in Alzheimer's disease and the substantia nigra of Parkinson's disease patients. The hyperactivation of microglia contributes to neurotoxicity. In the present study we tested the hypothesis that anti-inflammatory compounds modulate the progression of cell cycle and induce apoptosis of the activated cells. We investigated the effects of ibuprofen (non-steroidal anti-inflammatory drug) and apigenin (a flavonoid with anti-inflammatory and anti-proliferative properties) on the cell cycle of the murine microglial cell line BV-2. The findings indicate that apigenin-induced cell cycle arrest preferentially in the G2/M phase and ibuprofen caused S phase arrest. The binding of annexin V-FITC to the membranes of cells which indicates the apoptotic process were examined, whereas the DNA was stained with propidium iodide. Both apigenin and ibuprofen induced apoptosis significantly in early and late stages. The induction of apoptosis by ibuprofen and apigenin was confirmed using TUNEL assay, revealing that 25 microM apigenin and 250 microM ibuprofen significantly increased apoptosis in BV-2 cells. The results from the present study suggest that anti-inflammatory compounds might inhibit microglial proliferation by modulating the cell cycle progression and apoptosis.
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PMID:Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia. 1567 Jun 48

A decrease in myocardial uptake of iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) has been reported in idiopathic Parkinson's disease (PD) using 123I-MIBG myocardial scintigraphy. However, the patient with autosomal recessive juvenile parkinsonism (AR-JP), caused by the parkin gene, presented here showed normal 123I-MIBG myocardial uptake, suggesting that AR-JP is a distinct disease entity from PD. Although the clinical features of AR-JP are sometimes quite similar to those of late-onset idiopathic PD, 123I-MIBG myocardial scintigraphy may be a powerful tool to differentiate PD from other parkinsonian syndromes, including AR-JP.
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PMID:Preserved myocardial [123I]metaiodobenzylguanidine uptake in autosomal recessive juvenile parkinsonism: first case report. 1570 7


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