Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paraquat, N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, and rotenone have been shown to reproduce several features of Parkinson's disease in animal and cell culture models. Although these chemicals are known to perturb dopamine homeostasis and induce dopaminergic cell death, their molecular mechanisms of action are not well defined. We have previously shown that paraquat does not require functional dopamine transporter and does not inhibit mitochondrial complex I in order to mediate its toxic action (Richardson et al., 2005). In this study, we show that paraquat specifically oxidized the cytosolic form of thioredoxin and activated Jun N-terminal kinase (JNK), followed by caspase-3 activation. Conversely, 1-methyl-4-phenylpyridinium (MPP(+)) and rotenone oxidized the mitochondrial form of thioredoxin but did not activate JNK-mitogen-activated protein kinase and caspase-3. Loading cells with exogenous dopamine did not exacerbate the toxicity of any of these compounds. These data suggest that oxidative modification of cytosolic proteins is critical to paraquat toxicity, while oxidation of mitochondrial proteins is important for MPP(+) and rotenone toxicity. In addition, intracellular dopamine does not seem to exacerbate the toxicity of these dopaminergic neurotoxicants in this model.
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PMID:Divergent mechanisms of paraquat, MPP+, and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation. 1701 46

The critical observation in the pathology of Parkinson's disease (PD) is that neurodegeneration is largely restricted to dopaminergic neurons that develop cytoplasmic inclusions called Lewy bodies. These aggregations contain the protein alpha-synuclein. Furthermore, it is becoming apparent that alpha-synuclein expression levels are a major factor in PD pathogenesis. Patients with additional copies of the alpha-synuclein gene develop PD with a severity proportional to levels of alpha-synuclein overexpression. Similarly, overexpression of alpha-synuclein in in vitro and in vivo models has been shown to be toxic. However, little is known about the effects of reducing alpha-synuclein expression in human neurons. To investigate this, we have developed a system in which levels of alpha-synuclein can be acutely suppressed by using RNA interference (RNAi) in a physiologically relevant human dopaminergic cellular model. By using small interfering RNA (siRNA) molecules targeted to endogenous alpha-synuclein, we achieved 80% protein knockdown. We show that alpha-synuclein knockdown has no effect on cellular survival either under normal growth conditions over 5 days or in the presence of the mitochondrial inhibitor rotenone. Knockdown does, however, confer resistance to the dopamine transporter (DAT)-dependent neurotoxin N-methyl-4-phenylpyridinium (MPP(+)). We then demonstrate for the first time that alpha-synuclein suppression decreases dopamine transport in human cells, reducing the maximal uptake velocity (V(max)) of dopamine and the surface density of its transporter by up to 50%. These results show that RNAi-mediated alpha-synuclein knockdown alters cellular dopamine homeostasis in human cells and may suggest a mechanism for the increased survival in the presence of MPP(+), a toxin used extensively to model Parkinson's disease.
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PMID:RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. 1713 21

Mutations in the gene for DJ-1 have been associated with early-onset autosomal recessive parkinsonism. Previous studies of null DJ-1 mice have shown alterations in striatal dopamine (DA) transmission with no DAergic cell loss. Here we characterize a new line of DJ-1-deficient mice. A subtle locomotor deficit was present in the absence of a change in striatal DA levels. However, increased [(3)H]-DA synaptosomal uptake and [(125)I]-RTI-121 binding were measured in null DJ-1 vs. wild-type mice. Western analyses of synaptosomes revealed significantly higher dopamine transporter (DAT) levels in pre-synaptic membrane fractions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure exacerbated striatal DA depletion in null DJ-1 mice with no difference in DAergic nigral cell loss. Furthermore, increased 1-methyl-4-phenylpyridinium (MPP(+)) synaptosomal uptake and enhanced MPP(+) accumulation were measured in DJ-1-deficient vs. control striatum. Thus, under null DJ-1 conditions, DAT changes likely contribute to altered DA neurotransmission and enhanced sensitivity to toxins that utilize DAT for nigrostriatal entry.
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PMID:Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter. 1756 Jul 90

Parkinson's disease (PD) is a movement disorder resulting from nigrostriatal dopaminergic neurodegeneration. The impairment of mitochondrial function and dopamine synaptic transmission are involved in the pathogenesis of PD. Two mitochondrial inhibitors, 1-methyl-4-phenylpyridine (MPP(+)) and rotenone, have been used to induce dopaminergic neuronal death both in in vitro and in vivo models of PD. Because the uptake of MPP(+) is mediated by the dopamine transporter (DAT), we used a cell-permeable rotenone-induced PD model to investigate the role of DAT and dopamine D2 receptor (D2R) on dopaminergic neuronal loss. Rotenone subcutaneously infused for 14 days induced PD symptoms in rats, as indicated by reduced spontaneous locomotor activity (hypokinesis), loss of tyrosine hydroxylase (TH, a marker enzyme for dopamine neurons) immunoreactivity in the substantia nigra and striatum, obvious alpha-synuclein accumulation, downregulated DAT protein expression, and upregulated D2R expression. Interestingly, rotenone also caused significant noradrenergic neuronal loss in the locus coeruleus. Melatonin, an antioxidant, prevented nigrostriatal neurodegeneration and alpha-synuclein aggregation without affecting the rotenone-induced weight loss and hypokinesis. However, rotenone-induced hypokinesis was markedly reversed by the DAT antagonist nomifensine and body weight loss was attenuated by the D2R antagonist sulpiride. In addition, both antagonists significantly prevented the reduction of striatal TH or DAT immunoreactivity but not the loss of nigral TH- and DAT-immunopositive neurons. These results suggested that oxidative stress and DAT downregulation are involved in the rotenone-induced pathogenesis of nigrostriatal dopaminergic neurodegeneration, whereas D2R upregulation may simply represent a compensatory response.
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PMID:Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. 1828 73

Cocktail recipes containing Psoralea corylifolia seeds (PCS) are used to empirically treat Parkinson disease. A PCS isolate Delta(3),2-hydroxybakuchiol (BU) can inhibit dopamine uptake in dopamine transporter (DAT) transfected Chinese hamster ovary (CHO) cells, and dopamine reuptake blockade may provide an alternative approach for ameliorating parkinsonism. Here, we assessed the potential dopaminergic neuroprotective, and antiparkinsonian-like activity of BU. BU sample size was increased by using a scale-up extraction paradigm. Pharmacologically, BU significantly protected SK-N-SH cells from 1-methyl-4-phenylpyridinium (MPP(+)) insult, produced striking inhibitory actions on dopamine/norepinephrine uptake and WIN35,428 binding in synaptosomes on in vivo administration, and significantly preventing poor performance on rotarod and dopaminergic loss in substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice. BU acts by protecting dopaminergic neurons from MPP(+) injury and preventing against MPTP-induced behavioral and histological lesions in the Parkinson's disease (PD) model, possibly by inhibiting monoamine transporters. These findings suggest that BU could be meaningful in PD treatment.
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PMID:In vitro dopaminergic neuroprotective and in vivo antiparkinsonian-like effects of Delta 3,2-hydroxybakuchiol isolated from Psoralea corylifolia (L.). 1932 17

Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by the selective loss of dopaminergic neurons of the nigrostriatal pathway. Epidemiological studies have shown an inverse relationship between coffee consumption and susceptibility to PD. Cytochrome P450 1A2 (CYP1A2) is involved in caffeine metabolism and its clearance. Caffeine, on the other hand, antagonizes adenosine A(2A) receptor and regulates dopamine signaling through dopamine transporter (DAT). The present study was undertaken to investigate the expression of CYP1A2, adenosine A(2A) receptor and DAT in mouse striatum and to assess their levels in 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropryridine (MPTP) treated mouse striatum with and without caffeine treatment. The animals were treated intraperitoneally daily with caffeine (20 mg/kg) for 8 weeks, followed by MPTP (20 mg/kg)+caffeine (20 mg/kg) for 4 weeks or vice versa, along with respective controls. Tyrosine hydroxylase immunoreactivity, levels of dopamine and 1-methyl 4-phenylpyridinium ion (MPP(+)), expressions of CYP1A2, adenosine A(2A) receptor and DAT and CYP1A2 catalytic activity were measured in control and treated mouse brain. Caffeine partially protected MPTP-induced neurodegenerative changes and modulated MPTP-mediated alterations in the expression and catalytic activity of CYP1A2, expression of adenosine A(2A) receptor and DAT. The results demonstrate that caffeine alters the striatal CYP1A2, adenosine A(2A) receptor and DAT expressions in mice exposed to MPTP.
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PMID:Effect of caffeine on the expression of cytochrome P450 1A2, adenosine A2A receptor and dopamine transporter in control and 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine treated mouse striatum. 1952 64

LUHMES cells are conditionally-immortalized non-transformed human fetal cells that can be differentiated to acquire a dopaminergic neuron-like phenotype under appropriate growth conditions. After differentiation by GDNF and cyclic adenosine monophosphate, LUHMES were sensitive to 1-methyl-4-phenylpyridinium (MPP(+)) toxicity at < or =5 microM, but resistant to the parental compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The high homogeneity and purity of the cultures allowed the detection of metabolic changes during the degeneration. Cellular ATP dropped in two phases after 24 and 48 h; cellular glutathione (GSH) decreased continuously, paralleled by an increase in lipid peroxidation. These events were accompanied by a time-dependent degeneration of neurites. Block of the dopamine transporter by GBR 12909 or mazindol completely abrogated MPP(+) toxicity. Inhibition of de novo dopamine synthesis by alpha-methyl-l-tyrosine or 3-iodo-l-tyrosine attenuated toxicity, but did not reduce the initial drop in ATP. Inhibition of mixed lineage kinases by CEP1347 completely prevented the MPP(+)-induced loss of viability and intracellular GSH, but failed to attenuate the initial drop of ATP. For the quantitative assessment of neurite degeneration, an automated imaging-based high content screening approach was applied and confirmed the findings made by pharmacological interventions in this study. Our data indicate that inhibition of mitochondrial ATP synthesis is not sufficient to trigger cell death in MPP(+)-treated LUHMES.
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PMID:Requirement of a dopaminergic neuronal phenotype for toxicity of low concentrations of 1-methyl-4-phenylpyridinium to human cells. 1964 8

Oxidative stress is regarded as a mediator of nerve cell death in several neurodegenerative disorders, such as Parkinson's disease. Sesamin, a lignan mainly found in sesame oil, is currently under study for its anti-oxidative and possible neuroprotective properties. We used 1-methyl-4-phenyl-pyridine (MPP(+)) ion, the active metabolite of the potent parkinsonism-causing toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, to produce oxidative stress and neurodegeneration in neuronal PC12 cells, which express dopamine, as well as neurofilaments. Our results show that picomolar doses of sesamin protected neuronal PC12 cells from MPP(+)-induced cellular death, as revealed by colorimetric measurements and production of reactive oxygen species. We also demonstrated that sesamin acted by rescuing tyrosine hydroxylase levels from MPP(+)-induced depletion. Sesamin, however, did not modulate dopamine transporter levels, and estrogen receptor-alpha and -beta protein expression. By examining several parameters of cell distress, we found that sesamin also elicited a strong increase in superoxide dismutase activity as well as protein expression and decreased catalase activity and the MPP(+) stimulated inducible nitric oxide synthase protein expression, in neuronal PC12 cells. Finally, sesamin possessed significant anti-inflammatory properties, as disclosed by its potential to reduce MPP(+)-induced interleukin-6 mRNA levels in microglia. From these studies, we determined the importance of the lignan sesamin as a neuroprotective molecule and its possible role in complementary and/or preventive therapies of neurodegenerative diseases.
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PMID:Sesamin modulates tyrosine hydroxylase, superoxide dismutase, catalase, inducible NO synthase and interleukin-6 expression in dopaminergic cells under MPP+-induced oxidative stress. 1979 9

The protective effect of an iridoid catalpol extracted and purified from the traditional Chinese medicinal herb Rehmannia glutinosa on the neuronal degeneration of nigral-striatal dopaminergic pathway was studied in a chronic 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)/probenecid C57BL/6 mouse model and in 1-methyl-4-phenylpyridimium (MPP(+)) intoxicated cultured mesencephalic neurons. Rotarod performance revealed that the locomotor ability of mice was significantly impaired after completion of model production and maintained thereafter for at least 4 weeks. Catalpol orally administered for 8 weeks (starting from the second week of model production) dose dependently improved the locomotor ability. HPLC revealed that catalpol significantly elevated striatal dopamine levels without changing the metabolite/dopamine ratios. Nor did it bind to dopamine receptors. Therefore it is unlikely that catalpol resembles any of the known compounds for treating Parkinsonism. Instead, catalpol dose dependently raised the tyrosine hydroxylase (TH) neuron number in substantia nigra pars compacta (SNpc), the striatal dopamine transporter (DAT) density and the striatal glial cell derived neurotrophic factor (GDNF) protein level. Linear regression revealed that both the TH neuron number and DAT density were positively correlated to the GDNF level. In the cultured mesencephalic neurons, MPP(+) decreased the dopaminergic neuron number and shortened the neurite length, whereas catalpol showed protective effect dose dependently. Furthermore, the expression of GDNF mRNA was up-regulated by catalpol to a peak nearly double of normal control in neurons intoxicated with MPP(+) for 24 h but not in normal neurons. The GDNF receptor tyrosine kinase RET inhibitor 4-amino-5-(4-methyphenyl)-7-(t-butyl)-pyrazolo-[3,4-d]pyrimidine (PP1) abolished the protective effect of catalpol either partially (TH positive neuron number) or completely (neurite length). Taken together, catalpol improves locomotor ability by attenuating the neuronal degeneration of nigral-striatal dopaminergic pathway, and this attenuation is at least partially through elevating the striatal GDNF expression.
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PMID:Catalpol attenuates MPTP induced neuronal degeneration of nigral-striatal dopaminergic pathway in mice through elevating glial cell derived neurotrophic factor in striatum. 2012 1

In the present work we report the generation of a new line of alpha-synuclein (alpha-SYN) transgenic mice in which the human wild-type alpha-SYN cDNA is expressed under the control of a tyrosine hydroxylase (TH) promoter. We provide evidence that the ectopic protein is found in TH expressing neurons of both central and peripheral nervous systems. The transgene is expressed very early in development coinciding with the activity of the TH promoter and in the adult brain the human protein distributes normally to the nerve endings and cell bodies of dopaminergic nigral neurons without any evidence of abnormal aggregation. Our results indicate that expression of human wild-type alpha-SYN does not affect normal development or maintenance of TH immunoreactive nigral neurons, striatal dopamine content, or locomotor activity. Systemic administration of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a loss of TH immunoreactive nigral neurons and terminals and of dopamine levels to the same degree in both transgenic and non-transgenic adult mice. Intoxication also results in a similar loss of cardiac noradrenaline in both genotypes. Surprisingly, cultured transgenic ventral mesencephalic fetal dopaminergic neurons exhibit complete resistance to cell death induced by 1-methyl-4-phenylpyridinium ion (MPP(+)) intoxication, without changes in dopamine transporter (DAT) surface levels. Interestingly, this protection is not observed in other populations of catecholaminergic neurons such as peripheral sympathetic neurons, despite their high sensitivity to MPP(+)in vitro.
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PMID:Prosurvival effect of human wild-type alpha-synuclein on MPTP-induced toxicity to central but not peripheral catecholaminergic neurons isolated from transgenic mice. 2015 26


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