Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:28289-54-5 (MPTP)
 5,211 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mild heat shock preconditioning has been shown to induce thermotolerance and protection against a number of cytotoxic agents that may induce cell death by either apoptosis or necrosis. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that selectively targets dopaminergic cells of the substantia nigra and, as such, it is often used to induce neuronal cell death in models of Parkinson's disease. PC12 cells were heat-shocked for 1 h at 41.5 degrees C. This led to a rapid induction of Hsp25 and Hsp70. Levels of these proteins remained elevated for at least 24 h post heat shock. Treatment of PC12 cells with 1-methyl-4-phenylpyridinium (MPP(+)), the active metabolite of MPTP, resulted in cell death. Morphological analysis and the lack of caspase activity suggested that cell death was by necrosis. Heat shocking the cells 6 h prior to addition of MPP(+) significantly inhibited the induction of cell death by MPP(+). These results indicated that heat shock is protective against MPP(+) neurotoxicity in PC12 cells.
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PMID:Heat shock protects PC12 cells against MPP+ toxicity. 1464 38

In this study, we investigated the molecular mechanisms of toxicity of 1-methyl-4-phenylpyridinium (MPP(+)), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes Parkinson-like symptoms in experimental animals and humans. We used rat cerebellar granule neurons as a model cell system for investigating MPP(+) toxicity. Results show that MPP(+) treatment resulted in the generation of reactive oxygen species from inhibition of complex I of the mitochondrial respiratory chain, and inactivation of aconitase. This, in turn, stimulated transferrin receptor (TfR)-dependent iron signaling via activation of the iron-regulatory protein/iron-responsive element interaction. MPP(+) caused a time-dependent depletion of tetrahydrobiopterin (BH(4)) that was mediated by H(2)O(2) and transferrin iron. Depletion of BH(4) decreased the active, dimeric form of neuronal nitric-oxide synthase (nNOS). MPP(+)-mediated "uncoupling" of nNOS decreased *NO and increased superoxide formation. Pretreatment of cells with sepiapterin to promote BH(4) biosynthesis or cell-permeable iron chelator and TfR antibody to prevent iron-catalyzed BH(4) decomposition inhibited MPP(+) cytotoxicity. Preincubation of cerebellar granule neurons with nNOS inhibitor exacerbated MPP(+)-induced iron uptake, BH(4) depletion, proteasomal inactivation, and apoptosis. We conclude that MPP(+)-dependent aconitase inactivation, Tf-iron uptake, and oxidant generation result in the depletion of intracellular BH(4), leading to the uncoupling of nNOS activity. This further exacerbates reactive oxygen species-mediated oxidative damage and apoptosis. Implications of these results in unraveling the molecular mechanisms of neurodegenerative diseases (Parkinson's and Alzheimer's disease) are discussed.
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PMID:1-Methyl-4-phenylpyridinium-induced apoptosis in cerebellar granule neurons is mediated by transferrin receptor iron-dependent depletion of tetrahydrobiopterin and neuronal nitric-oxide synthase-derived superoxide. 1475 97

1-Methyl-4-phenylpyridinium (MPP(+)) ion, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is produced by monoamine oxidase B in astrocytes. MPP(+) causes a selective dopaminergic neurodegeneration, the pathophysiologic hallmark of Parkinson disease. However, the toxic effect of MPP(+) on astrocytes remains unclear. Here, we examined the effect of MPP(+) on human astrocytoma U373MG cells, with particular attention to the temporal interaction of glutathione (GSH) and reactive oxygen species (ROS) (H2O2 and O). MPP(+) induced astrocyte apoptosis in a dose-dependent manner 48 hr after treatment. Distinctive early (<6 hr) and late (24-48 hr) responses were observed. ROS production and the oxidized GSH (GSSG)/GSH ratio, indicators of oxidative stress, rose dramatically after 24 hr of MPP(+) exposure, whereas the H2O2 level transiently decreased at 6 hr. ROS overproduction and GSH dysfunction were concomitantly associated with caspase-3 activation and finally led to cell apoptosis. Moreover, GSH depletion by diethyl maleate, but not buthionine sulfoximine, caused cells to die quickly and potentiated the cytotoxicity of MPP(+). Co-treatment with melatonin, a known antioxidant secreted by the pineal gland, significantly prevented cell apoptosis by inhibiting oxidative stress and caspase-3 activation, but it did not affect that the early changes due to MPP(+) treatment. Our results demonstrate that in astrocytes, GSH is involved in the early decrease and late increase in ROS levels induced by MPP(+) treatment. Melatonin remedies the dysfunction of GSH system to block caspase-3 activation and cell apoptosis induced by oxidative stress during the long-term exposure of MPP(+).
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PMID:Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP(+) treatment in human astrocytoma U373MG cells. 1496 63

We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.
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PMID:Dopamine agonist 3-PPP fails to protect against MPTP-induced toxicity. 1500 33

The neuropathology of Parkinson's Disease has been modeled in experimental animals following MPTP treatment and in dopaminergic cells in culture treated with the MPTP neurotoxic metabolite, MPP(+). MPTP through MPP(+) activates the stress-activated c-Jun N-terminal kinase (JNK) pathway in mice and SH-SY5Y neuroblastoma cells. Recently, it was demonstrated that CEP-1347/KT7515 attenuated MPTP-induced nigrostriatal dopaminergic neuron degeneration in mice, as well as MPTP-induced JNK phosphorylation. Presumably, CEP-1347 acts through inhibition of at least one upstream kinase within the mixed lineage kinase (MLK) family since it has been shown to inhibit MLK 1, 2 and 3 in vitro. Activation of the MLK family leads to JNK activation. In this study, the potential role of MLK and the JNK pathway was examined in MPP(+)-induced cell death of differentiated SH-SY5Y cells using CEP-1347 as a pharmacological probe and dominant negative adenoviral constructs to MLKs. CEP-1347 inhibited MPP(+)-induced cell death and the morphological features of apoptosis. CEP-1347 also prevented MPP(+)-induced JNK activation in SH-SY5Y cells. Endogenous MLK 3 expression was demonstrated in SH-SY5Y cells through protein levels and RT-PCR. Adenoviral infection of SH-SY5Y cells with a dominant negative MLK 3 construct attenuated the MPP(+)-mediated increase in activated JNK levels and inhibited neuronal death following MPP(+) addition compared to cultures infected with a control construct. Adenoviral dominant negative constructs of two other MLK family members (MLK 2 and DLK) did not protect against MPP(+)-induced cell death. These studies show that inhibition of the MLK 3/JNK pathway attenuates MPP(+)-mediated SH-SY5Y cell death in culture and supports the mechanism of action of CEP-1347 as an MLK family inhibitor.
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PMID:Inhibition of mixed lineage kinase 3 attenuates MPP+-induced neurotoxicity in SH-SY5Y cells. 1501 67

Endogenous or exogenous beta-carboline (betaC) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease (PD). We addressed the importance of the dopamine transporter (DAT) for selective dopaminergic toxicity by testing the differential cytotoxicity and cellular uptake of 12 betaCs in human embryonic kidney HEK-293 cells ectopically expressing the DAT gene. Cell death was measured using [4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays, and uptake by a fluorescence-based uptake assay. All betaCs and MPP(+) showed general cytotoxicity in parental HEK-293 cells after 72 h with half-maximal toxic concentrations (TC(50) values) in the upper micromolar range. Besides MPP(+), only 2[N]-methylated compounds showed enhanced cytotoxicity in DAT expressing HEK-293 cells with 1.3- to 4.5-fold reduction of TC(50) values compared with parental cell line. The rank order of selectivity was: MPP(+) >> 2[N],9[N]-dimethyl-harminium > 2[N]-methyl-harminium > 2[N],9[N]-dimethyl-harmanium = 2[N]-methyl-norharmanium > 2[N]-methyl-harmanium > 2[N],9[N]-dimethyl-norharminium. Consistently, only 2[N]-methylated betaCs were transported into the cell through the DAT with up to five times greater K(m) and 12-220 times smaller V(max) values compared with dopamine and MPP(+). There was a weak relation of DAT-mediated selectivity with the affinity of betaCs at the DAT (K(m)), but not with V(max). Our data suggest that DAT-mediated cellular uptake of 2[N]-methylated betaCs represents a potential mechanism for selective toxicity towards dopaminergic neurons and may be relevant for the pathogenesis of Parkinson's disease.
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PMID:Dopamine transporter-mediated cytotoxicity of beta-carbolinium derivatives related to Parkinson's disease: relationship to transporter-dependent uptake. 1508 25

The impact of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) in the pathology of Parkinson's disease (PD) and in MPTP neurotoxicity remains unclear. Here, male TNF-alpha (-/-) deficient mice and C57bL/6 mice were treated with MPTP (4 x 15 mg/kg, 24 h intervals) and in one series, thalidomide was administered to inhibit TNF-alpha synthesis. Real-time RT-PCR revealed that the striatal mRNA levels of TNF-alpha, of the astrocytic marker glial fibrillary acidic protein (GFAP) and of the marker for activated microglia, macrophage antigen complex-1 (MAC-1), were significantly enhanced after MPTP administration. Thalidomide (50 mg/kg, p.o.) partly protected against the MPTP-induced dopamine (DA) depletion, and TNF-alpha (-/-) mice showed a significant attenuation of striatal DA and DA metabolite loss as well as striatal tyrosine hydroxylase (TH) fiber density, but no difference in nigral TH and DA transporter immunoreactivity. TNF-alpha deficient mice suffered a lower mortality (10%) compared to the high mortality (75%) seen in wild-type mice after acute MPTP treatment (4 x 20 mg/kg, 2 h interval). HPLC measurement of MPP(+) levels revealed no differences in TNF-alpha (-/-), wild-type and thalidomide treated mice. This study demonstrates that TNF-alpha is involved in MPTP toxicity and that inhibition of TNF-alpha response may be a promising target for extending beyond symptomatic treatment and developing anti-parkinsonian drugs for the treatment of the inflammatory processes in PD.
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PMID:Genetic ablation of tumor necrosis factor-alpha (TNF-alpha) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. 1514 Jan 82

1-Methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces cell death and inhibition of cell proliferation in various cells. However, the mechanism whereby MPP(+) inhibits cell proliferation is still unclear. In this study, we found that MPP(+) suppressed the proliferation with accumulation in G(1) phase without inducing cell death in p53-deficient MG63 osteosarcoma cells. MPP(+) induced hypophosphorylation of retinoblastoma protein and rapidly down-regulated the protein but not mRNA levels of cyclin D1 in MG63 cells. The down-regulation of cyclin D1 protein was suppressed by a proteasome inhibitor, MG132. The cyclin D1 down-regulation by MPP(+) was also observed in p53-positive PC12, HeLa S3, and HeLa rho(0) cells, which are a subclone of HeLa S3 lacking mitochondrial DNA. Moreover, MPP(+) dephosphorylated Akt in PC12 cells, which was rescued by the pretreatment with nerve growth factor. In addition, the pretreatment with nerve growth factor or lithium chloride, a glycogen synthase kinase-3beta inhibitor, suppressed the cyclin D1 down-regulation caused by MPP(+). Our results demonstrate that MPP(+) induces cell cycle arrest independently of its mitochondrial toxicity or the p53 status of the target cells, but rather through the proteasome- and phosphatidylinositol 3-Akt-glycogen synthase kinase-3beta-dependent cyclin D1 degradation.
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PMID:Proteasome-dependent degradation of cyclin D1 in 1-methyl-4-phenylpyridinium ion (MPP+)-induced cell cycle arrest. 1524 82

Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder with no clear etiology. Pathological hallmarks of the disease include the loss of dopaminergic neurons from the substantia nigra (SN) and the presence of Lewy bodies (LBs) (alpha-synuclein and ubiquitin-positive, eosinophilic, cytoplasmic inclusions) in many of the surviving neurons. Experimental modeling of PD neurodegeneration using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenyl-pyridinium (MPP(+)) has identified changes in gene expression of different endoplasmic reticulum (ER) stress proteins associated with MPTP- and PD-related neurodegeneration. We show that the protein disulfide isomerase (PDI) family member pancreatic protein disulfide isomerase (PDIp), previously considered exclusively expressed in pancreatic tissue, is uniquely upregulated among PDI family members within 24 h following exposure of retinoic acid (RA)-differentiated SH-SY5Y human neuroblastoma cells to either 1 mM MPP(+) or 10 microM of the highly specific proteasome inhibitor lactacystin. RT-PCR confirms PDIp expression in brain of post-mortem human PD subjects and immunohistochemical studies demonstrate PDIp immunoreactivity in LBs. Collectively, these findings suggest that increased PDIp expression in dopaminergic (DA) neurons might contribute to LB formation and neurodegeneration, and that this increased PDIp expression may be the result of proteasome impairment.
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PMID:Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology. 1535 26

The carrier molecule that transports dopamine (DA) into dopamine neurons by an electrogenic, Na(+)- and Cl(-)-transport-coupled mechanism is known as the dopamine transporter (DAT). This uptake system is exclusively expressed in DA neurons with significantly higher levels of DAT expression in cells of the substantia nigra pars compacta than those of the ventral tegmental area and arcuate hypothalamic neurons. The expression density of DAT strongly correlates with the extent of DA cell loss in Parkinson's disease (PD). There are also DAT gene polymorphisms associated with PD. These data suggest a role of the DAT in the pathogenesis of PD. Though selective for its respective neurotransmitter, the DAT can also transport synthetic/natural analogues of the transmitter. Should such compounds interact with vital intracellular structures, their penetration into the neuron might have significant consequences. This sequence of toxic events could indeed demonstrated for the synthetic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces selective degeneration of DA neurons characteristic of PD. Dopaminergic toxicity of its active metabolite 1-methyl-4-pyridinium (MPP(+)) is mediated by the DAT through accumulation into DA neurons, where it inhibits mitochondrial complex I activity. Various endogenous and exogenous heterocyclic molecules, which are structurally related to MPTP/MPP(+), such as isoquinolines and beta-carbolines, have been reported to exhibit similar toxic properties on DA cells, which are conferred by their uptake by the DAT. Taken together, there is large body of evidence from morphological, molecular biological and toxicological studies indicating that the DAT might be responsible for the selectivity of DA cell death in PD.
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PMID:Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration. 1548 Aug 38


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