Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isatin is an endogenous indole that is increased in stress, inhibits monoamine oxidase (MAO) B and improves bradykinesia and striatal dopamine levels in rat models of Parkinson's disease. Consequently, it has been suggested that isatin might be a possible treatment for Parkinson's disease although little is known about its effects on neural cell growth and survival. The aim of this study was to investigate the survival of dopaminergic human neuroblastoma (SH-SY5Y) cells following treatment with increasing concentrations of isatin. SH-SY5Y cells were exposed to isatin for defined time points, after which cell survival was determined by MTT assay. A combination of Annexin V binding and propidium iodide (PI) exclusion was used to distinguish apoptosis from necrosis in flow cytometry experiments and FACS profiles of permeabilised PI-labelled cells were employed for the assessment of cell cycle distribution. Isatin treatment (1-400 microM) for 24h induced a significant dose-dependent increase in MTT metabolism by SH-SY5Y cells in culture, but this was not due to an increase in cell division. At the higher concentrations (200-400 microm) isatin triggered cell death, although MTT metabolism was still increased in the culture, suggesting that surviving cells were hypermetabolic. Following a longer (48 h) exposure, isatin was found to cause cell death in a dose-dependent manner; at lower concentrations (50 microM), the predominant mode of cell death was apoptosis while at the highest concentration (400 microm) increasing numbers of necrotic cells were also evident. Thus, in dopaminergic SH-SY5Y cells isatin induces cell death in dose- and time-dependent manner. This death occurred as a continuum of survival, apoptosis and necrosis. Our results re-emphasise that caution should be exercised when considering high doses of isatin as a putative anti-Parkinson's disease therapeutic.
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PMID:Isatin, an endogenous monoamine oxidase inhibitor, triggers a dose- and time-dependent switch from apoptosis to necrosis in human neuroblastoma cells. 1587 76

Bak Foong Pills (BFP), a traditional Chinese medicine used for centuries for the enhancement of women's health, was shown to display neuro-protective activity in the 1-methyl-4-phenyl-1,2,4,6,-tetrahydro-pyridine (MPTP)-induced mouse model in a previous study. In order to elucidate its mechanism of action, we investigated the anti-apoptotic properties of Bak Foong Pills and its main ingredients, including Panax ginseng, Angelica sinensis, Glycyrrhiza uralensis, and Ligusticum chuanxiong, in the 6-hydroxydopamine (6-OHDA)-treated PC12 cell model. The addition of the neurotoxin could cause significant cell death and reduction of cell proliferation, as shown in the results determined by MTT assay, nitric oxide (NO) measurement and flow cytometric propidium iodine (PI) staining analysis, while pre-treatment of PC12 cell with either BFP or its main ingredients prevented the toxicity to some degree. In addition, the neurotoxin caused an elevated activation of caspase-3, the key enzyme for activation of the cellular apoptotic cascade, whereas BFP or its main ingredients inhibited the activation of caspase-3. These results strongly indicate that BFP and its main ingredients may provide a useful therapeutic strategy for the treatment of neurodegenerative diseases, such as Parkinson's disease.
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PMID:Anti-apoptotic activity of Bak Foong Pills and its ingredients on 6-hydroxydopamine-induced neurotoxicity in PC12 cells. 1615 79

Neurogenesis in the adult brain occurs within the two principal neurogenic regions: the hippocampus and the subventricular zone of the lateral ventricles. The occurrence of adult neurogenesis in non-neurogenic regions, including the midbrain, remains controversial, but isolation of neural stem cells (NSCs) from several parts of the adult brain, including the substantia nigra, has been reported. Nevertheless, it is unclear whether adult NSCs do have the capacity to produce functional dopaminergic neurons, the cell type lost in Parkinson's disease. Here, we describe the isolation, expansion, and in vitro characterization of adult mouse tegmental NSCs (tNSCs) and their differentiation into functional nerve cells, including dopaminergic neurons. These tNSCs showed neurosphere formation and expressed high levels of early neuroectodermal markers, such as the proneural genes NeuroD1, Neurog2, and Olig2, the NSC markers Nestin and Musashi1, and the proliferation markers Ki67 and BrdU (5-bromo-2-deoxyuridine). The cells showed typical propidium iodide-fluorescence-activated cell sorting analysis of slowly dividing cells. In the presence of selected growth factors, tNSCs differentiated into astroglia, oligodendroglia, and neurons expressing markers for cholinergic, GABAergic, and glutamatergic cells. Electrophysiological analyses revealed functional properties of mature nerve cells, such as tetrodotoxin-sensitive sodium channels, action potentials, as well as currents induced by GABA (gamma-aminobutyric acid), glutamate, and NMDA (N-methyl-D-aspartate). Clonal analysis demonstrated that individual NSCs retain the capacity to generate both glia and neurons. After a multistep differentiation protocol using co-culture conditions with PA6 stromal cells, a small number of cells acquired morphological and functional properties of dopaminergic neurons in culture. Here, we demonstrate the existence of adult tNSCs with functional neurogenic and dopaminergic potential, a prerequisite for future endogenous cell replacement strategies in Parkinson's disease.
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PMID:Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons. 1637 95

Because clinical features of parkinsonism can occur in other forms of parkinsonian syndromes in addition to Parkinson's disease, neuroimaging may have a role in determining true disease status. Iodine-123 ((123)I) (2beta-carboxymethoxy-3beta-[4-iodophenyl] tropane) or ((123)I) beta-CIT is a recently developed diagnostic biomarker of Parkinson's disease that provides in vivo information about nigrostriatal degeneration. In clinical trials, beta-CIT single photon emission computed tomography (SPECT) has been shown to be a highly sensitive diagnostic tool in differentiating clinically probable Parkinson's disease from normal subjects and essential tremor patients. As a tool for differentiating Parkinson's disease from atypical parkinsonian syndromes, ((123)I) beta-CIT SPECT may have more limited use because of more extensive postsynaptic pathology in the latter. Differentiating among various parkinsonian syndromes may be improved by methodological refinements, a combined strategy of imaging presynaptic and postsynaptic sites, or by metabolic imaging.
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PMID:How useful is (123I) beta-CIT SPECT in the diagnosis of Parkinson's disease? 1659 82

The aim of this study was to evaluate the brain scintiscan images with (123)I-ioflupane for the diagnosis of patients with early Parkinson's disease (PD). Sixteen patients were studied, nine males and seven females, aged between 38-81 y (mean age: 64 y). All patients underwent thyroid blocking by oral administration of 120 mg potassium iodide before and 24 h after the intravenous (iv) injection of 110-185 MBq/70 kg patient's weight, of (123)I-ioflupane. To check the correct biodistribution of the radiopharmaceutical, whole-body scans were performed at 15 min and 2-3 h after the administration of the radiopharmaceutical. All patients underwent brain single photon emission tomography (SPET) scans on a SPET gamma-camera 3-5 h after (123)I-ioflupane administration. To compensate for scatter and to avoid artifacts, the filtering and reconstructing procedures of the images were performed individually for each patient. Brain SPET results were evaluated semi-quantitatively using different indices. The morphology of the nigrostriatum (NS) area was also examined visually. The (123)I-ioflupane uptake by the affected nigrostriatum (ANS) was compared to a similar area at the occipital (Occ) brain section and to a similar area at the opposite NS. When the value of ANS/Occ was within the confidence limit of 1.507-1.636 and the value of ANS/NNS was within the limit of 0.755-0.889, PD was diagnosed (P<0.05). Thirteen of our patients were diagnosed as having PD and were given l-DOPA treatment. In the remaining patients the diagnosis of PD was rejected due to normal scintigraphic and morphologic findings of the NS area. The interest of this article lies in the following: The correct distribution of the radiopharmaceutical was confirmed by whole body scintiscan. Parameters for better quality of imaging were individually selected for each patient. The morphology of the NS areas, as estimated visually by us, was in accord with the scintigraphic (123)I-ioflupane uptake. The diagnosis of PD was clinically confirmed after treatment with l-DOPA in a seven month follow up period. Results from the small number of cases studied showed: 93% sensitivity and maximum specificity for the diagnosis of PD.
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PMID:The brain scintiscan with iodine-123-ioflupane to diagnose early Parkinson's disease; seven months follow up. First results in Bulgaria. 1661 91

NAD(P)H quinone oxidoreductase 1 (NQO1) can metabolize dopamine-derived quinones (DAQ) and absence of NQO1 due to the NQO1*2 polymorphism has been suggested to be a risk factor for Parkinson's disease. In order to define whether NQO1 plays a protective role in dopamine toxicity, we have examined the potential role of NQO1 in the SK-N-MC human neuroblastoma cell line. SK-N-MC cells were stably transfected with NQO1 to generate stable clones with NQO1 enzymatic activity of 245 nmol/mgmin while vector control and parental cells had NQO1 activities of less than 12 nmol/mgmin. Incubation of dopamine for 24 h in both parental and vector control SK-N-MC cells resulted in 85% and 72% cell death as assessed by annexin-V/propidium iodide analysis. In agreement, 88% and 84% of parental and vector control cells, respectively underwent loss of mitochondrial membrane potential (MMP) assessed by tetramethylrhodamine ethyl ester. In contrast, NQO1-transfected cells were resistant to dopamine toxicity and both cell death and loss of MMP were markedly abrogated in NQO1-transfected SK-N-MC cells. When dopamine was added to medium, oxygen uptake could be detected indicating autoxidation with concomitant formation of oxygen radicals and quinones. However, dopamine-induced cell death was not affected by the inclusion of either superoxide dismutase or catalase suggesting that superoxide and hydrogen peroxide were not involved in toxicity. Quinones formed in medium may exert toxicity extracellularly or intracellularly but the protective role of NQO1 argues for an intracellular mechanism. In summary, transfection of SK-N-MC cells with NQO1 protects against dopamine-induced toxicity.
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PMID:Overexpression of NQO1 protects human SK-N-MC neuroblastoma cells against dopamine-induced cell death. 1697 7

Oxidative stress plays crucial role in the pathogenesis of neurodegenerative diseases. However, the precise mechanism for an increased production of reactive oxygen species (ROS) under pathological conditions is not yet fully understood. We have recently demonstrated an implication of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a tumor suppressor, in ROS generation and neuronal apoptosis induced by staurosporine. These findings raised further interest whether PTEN functions as a common mediator of oxidative stress in neurodegenerative processes. To address this issue, neural cells were exposed to oxygen-glucose deprivation (OGD) and to the neurotoxin 1-methyl-4-phenylpyridinium iodide (MPP(+)), which mimic cerebral ischemia and Parkinson's disease, respectively. OGD for 4 h followed by 16 h of reoxygenation or incubation with MPP(+) (250 microM) for 48 h induced 33% and 45% neuronal death in rat hippocampal and in human dopaminergic SH-SY5Y neurons, respectively, accompanied by a gradual increase in the intracellular level of ROS. The increase in ROS by OGD and by MPP(+) did not cause oxidative inactivation of PTEN and thus, PTEN remains constitutively active. In support, the protein level of PTEN was not reduced in both cell cultures after challenging with OGD or MPP(+). Importantly, the elevated intracellular ROS levels and the neuronal death caused by OGD or by MPP(+) toxicity were significantly inhibited when PTEN was downregulated by a specific antisense oligonucleotide or by siRNA. Because SOD2 protein level is not altered either by knockdown of PTEN nor by an inhibition of the PI3K/Akt signalling, we suggest that SOD2 do not contribute to the pathomechanism of oxidative stress induced by PTEN or by inhibiting the related Akt signalling. The present study highlights PTEN as a crucial and common mediator of ROS generation and neuronal death and suggests that PTEN could become a potential therapeutic target for interfering with neurodegeneration.
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PMID:Implication of PTEN in production of reactive oxygen species and neuronal death in in vitro models of stroke and Parkinson's disease. 1716 62

The loss of mitochondrial function has been implicated in a number of maladies such as Huntington's disease, Parkinson's disease (PD), cancer and cardiovascular disease. The objective of this research was to develop a radiolabeled mitochondrial probe. Two tracers, 7'-Z-iodorotenol and 7'-Z-iodorotenone, analogs of rotenone a natural product that inhibits Complex I of the mitochondrial electron transport chain, have been labeled with iodine-125 in 45-85% yield in a single step from the corresponding tributylstannyl precursor. In vivo distribution in adult male Sprague-Dawley rats for both compounds showed high accumulation in the heart (1.7-3.7 %ID/g at 1 h), a tissue with high mitochondrial content. Z-Iodorotenol did not washout of most tissues between 1 and 2 h postinjection, whereas Z-iodorotenone showed moderate washout (7-26%) over the same period. By 24 h, there was significant loss of both compounds from most tissues including the heart. Heart-to-blood, -lung and -liver ratios for Z-iodorotenone of 28.9, 10.7 and 2.4, respectively, were two- to fourfold higher than the Z-iodorotenol ratios. Compared to the current clinical perfusion tracers, 99mTc-sestamibi and 99mTc-tetrofosmin, Z-iodorotenone demonstrates similar 1 h heart accumulation and significantly higher heart-to-lung ratio (P<.001). Z-Iodorotenone heart-to-liver ratio is equivalent to 99mTc-sestamibi. 7'-Z-Iodorotenone possesses distribution characteristics of an improved tracer for SPECT perfusion studies.
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PMID:Mitochondrial avid radioprobes. Preparation and evaluation of 7'(Z)-[125I]iodorotenone and 7'(Z)-[125I]iodorotenol. 1721 Apr 67

The neuropathological hallmark of Parkinson's disease (PD) is the selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). In this study, using a microdialysis technique, we investigated whether an inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitrindazole (7-NI), could protect against DAergic neuronal damage induced by in vivo infusion of 1-methyl-4-phenylpiridinium iodide (MPP(+)) in freely moving rats. Experiments were performed over 2 days in three groups of rats: (a) nonlesioned, (b) MPP(+)-lesioned, and (c) 7-NI pretreated MPP(+)-lesioned rats. On day 1, control rats were perfused with an artificial CSF, while 1 mM MPP(+) was infused into the striatum for 10 min in the other two groups. The infusion of the MPP(+) produced a neurotoxic damage of the SNc DA neurons and increased striatal DA levels. On day 2, 1 mM MPP(+) was reperfused for 10 min into the striata of each rat group and DA levels were measured as an index of neuronal cell integrity. The limited rise of DA following MPP(+) reperfusion in the MPP(+)-lesioned rats was due to toxin-induced neuronal loss and was reversed by pretreatment with 7-NI (50 mg/kg, intraperitoneally) on day 1, indicating a neuroprotective effect by inhibiting NO formation. These results indicate that neuronally derived NO partially mediates MPP(+)-induced neurotoxicity. The similarity between the MPP(+) model and PD suggests that NO may play a significant role in its etiology.
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PMID:7-nitroindazole protects striatal dopaminergic neurons against MPP+-induced degeneration: an in vivo microdialysis study. 1726 89

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a metabolite of dopamine, may act as an endogenous neurotoxin and contribute to the etiology of Parkinson's disease (PD). The inverse relationship between smoking and PD prompted our previous investigation and the report of protective effects of nicotine against salsolinol-induced toxicity in cultured SH-SY5Y cells (Copeland et al., Neurotox. Res. 8:289, 2005). These cells, derived from human neuroblastoma cells, express dopaminergic activity and are used as a model of nigral dopaminergic cells, the major site of pathology in PD. The purpose of the current study was to investigate whether apoptotic or antiapoptotic mechanisms were responsible for the observed effects of salsolinol and nicotine, respectively. Moreover, it was of interest to determine whether the actions of nicotine are mediated through nicotinic receptors. SH-SY5Y cells were exposed to 0.4 or 0.7 mM salsolinol with and without pretreatment in combination of 0.1 mM nicotine and 0.1 mM mecamylamine and were exposed for 24 and 48 h. Various parameters including cell cycle perturbations (reflected in propidium iodide DNA staining); cell cycle regulator retinoblastoma protein (reflected in the Western blot), apoptosis (reflected in annexin V/propidium iodide staining followed by flow cytometry) were analyzed. Salsolinol caused an arrest of the cells in G1-phase of cell cycle and an increase in apoptotic indices, whereas pretreatment with nicotine attenuated or completely blocked the effects of salsolinol. Nicotine effects in turn, were totally blocked by mecamylamine (0.1 mM). The results suggest that apoptosis is a major mechanism for salsolinol-induced toxicity and that antiapoptotic effects of nicotine, mediated by nicotinic receptors, may play a primary role in its neuroprotective effects. Hence, nicotinic agonists in combination with other antiapoptotic agents may be of substantial benefit in at least a subpopulation of Parkinson patients.
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PMID:Antiapoptotic effects of nicotine in its protection against salsolinol-induced cytotoxicity. 1751


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