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)

In vivo administration of either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (MA) produces damage to the dopaminergic nervous system which may be due in part to the generation of reactive oxygen species (ROS). The resistance of superoxide dismutase (SOD) over-expressing transgenic mice to the effects of both MPTP and MA suggests the involvement of superoxide in the resulting neurotoxicity of both compounds. Superoxide can be converted by SOD to hydrogen peroxide, which itself can cause cellular degeneration by reacting with free iron to produce highly reactive hydroxyl radicals resulting in damage to proteins, nucleic acids and membrane phospholipids. Hydrogen peroxide has also been reported to be produced via inhibition of NADH dehydrogenase by MPP + formed during oxidation of MPTP by MAO-B and by dopamine auto-oxidation following MA-induced dopamine release from synaptic vesicles within nerve terminals. To test whether hydrogen peroxide is an important factor in the toxicity of either of these two neurotoxins, we created clonal PC12 lines expressing elevated levels of the hydrogen peroxide-reducing enzyme glutathione peroxidase (GSHPx). Elevation of GSHPx levels in PC12 was found to diminish the rise in ROS levels and lipid peroxidation resulting from MA but not MPTP treatment. Elevated levels of GSHPx also appeared to prevent decreases in transport-mediated dopamine uptake produced via MA administration as well as to attenuate toxin-induced cell loss as measured by either MTT reduction or LDH release. Our data, therefore, suggest that hydrogen peroxide production likely contributes to MA toxicity in dopaminergic neurons.
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PMID:Elevated expression of glutathione peroxidase in PC12 cells results in protection against methamphetamine but not MPTP toxicity. 919 Oct 89

MPP(+), the major metabolite of the Parkinsonism-inducing compound MPTP, responsible for the destruction of the nigrostriatal pathway in primates and rodents, has been assayed in isolated rat liver mitochondria in the presence of physiological concentrations of dopamine or analogous concentrations of melanin-dopamine. 5 microM MPP(+) in the presence of 70 microM dopamine or melanin-dopamine, but not alone, decreased the heat production and oxygen consumption of a mitochondrial suspension activated with succinate and ADP. Both dopamine and oxidized dopamine plus MPP(+) also decreased the mitochondrial reductive power measured with MTT. Mitochondrial swelling was observed, associated with an increase in membrane mitochondrial potential, as a synergistic effect between low concentrations of MPP(+) and dopamine. It is suggested that cytosolic dopamine, by itself or via its autooxidation products, may play a relevant role in the mitochondrial toxicity of MPP(+). A failure in the regulation of the storage/release of dopamine could aggravate a mitochondrial damage and trigger the neurodegenerative process underlying MPTP toxicity and Parkinson's disease.
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PMID:MPP(+)-induced mitochondrial dysfunction is potentiated by dopamine. 1067 5

Helicobacter pylori induces a number of disturbances in rodent gastric microcirculation in vivo. These events may result from direct necrotic or apoptotic damage to endothelial cells. This study therefore aimed to investigate the effects of genotypically different H. pylori strains on microvascular endothelial cell (MVEC) viability in vitro. Four H. pylori extracts were prepared from strains with different cagA or vacA status. MVECs were plated into 96-well plates and coincubated with 50 microl of extract or vehicle for 24, 48, 72, or 96 hr. An MPP assay quantified overall MVEC viability. The dual labeling of MVECs with propidium iodide and Hoechst 33342 distinguished between necrotic and apoptotic cell death, respectively, and allowed total number of viable cells to be determined. All strains of H. pylori decreased cell viability after 72 and 96 hr. Neither necrosis or apoptosis was observed. Counting total number of viable cells revealed decreased cell proliferation with all strains when compared to controls, again reaching significance at 72 and 96 hr. In conclusion, both the MTT assay and the diret cell counting technique demonstrated that all H. pylori strains induced cytostatic but not cytotoxic effects on MVECs. This suggests that microcirculatory disturbances observed in vivo may not be the result of direct endothelial cell damage. However, inhibition of angiogenesis may explain why ulcer healing is delayed in H. pylori-infected patients.
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PMID:Effects of genotypically different strains of Helicobacter pylori on human microvascular endothelial cells in vitro. 1127 Jul 94

Endogenous isoquinoline (IQ) 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-phenylpyridine (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. We addressed the importance of the DAT molecule for selective dopaminergic toxicity by testing the differential cytotoxicity of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (3, IQs; 4,3,4-dihydroisoquinolines and 15, 1,2,3,4-tetrahydroisoquinolines) as well as MPP(+) in non-neuronal and neuronal heterologous expression systems of the DAT gene (human embryonic kidney HEK-293 and mouse neuroblastoma Neuro-2A cells, respectively). Cell death was estimated using the MTT assay and the Trypan blue exclusion method. Nine isoquinolines and MPP(+) showed general cytotoxicity in both parental cell lines after 72hr with half-maximal toxic concentrations (TC(50) values) in the micromolar range. The rank order of toxic potency was: papaverine>salsolinol=tetrahydropapaveroline=1-benzyl-TIQ=norsalsolinol>tetrahydropapaverine>2[N]-methyl-salsolinol>2[N]-methyl-norsalsolinol>2[N]-Me-IQ(+)=MPP(+). Besides MPP(+), only the 2[N]-methylated compounds 2[N]-methyl-IQ(+), 2[N]-methyl-norsalsolinol and 2[N]-methyl-salsolinol showed enhanced cytotoxicity in both DAT expressing cell lines with 2- to 14-fold reduction of TC(50) values compared to parental cell lines. The rank order of selectivity in both cell systems was: MPP(+)>>2[N]-Me-IQ(+)>2[N]-methyl-norsalsolinol=2[N]-methyl-salsolinol. Our results suggest that 2[N]-methylated isoquinoline derivatives structurally related to MPTP/MPP(+) are selectively toxic to dopaminergic cells via uptake by the DAT, and therefore may play a role in the pathogenesis of Parkinson's disease.
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PMID:Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter. 1191 43

The neuroprotective effects of verbascoside, one of phenylpropanoid glucoside isolated from the Chinese herbal medicine Buddleja officinalis Maxim, on 1-methyl-4-phenylpyridinium ion (MPP(+)) induced apoptosis and oxidative stress in PC12 neuronal cells were investigated. Treatment of PC12 cells with MPP(+) for 48 h induced apoptotic death as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, the activation of caspase-3 measured by the caspase-3 activity assay kit, the reduction in mitochondrial membrane potential with laser scanning confocal microscopy and the increase in the extracellular hydrogen peroxide level. Simultaneous treatment with verbascoside markedly attenuated MPP(+)-induced apoptotic death, increased extracellular hydrogen peroxide level, the activation of caspase-3 and the collapse of mitochondrial membrane potential. These results strongly indicate that verbascoside may provide a useful therapeutic strategy for the treatment of oxidative stress-induced neurodegenerative disease such as Parkinson's disease.
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PMID:Protective effect of verbascoside on 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells. 1223 80

The neuroprotective effects of tubuloside B, one of the phenylethanoids isolated from the Chinese herbal medicine Cistanche salsa, on 1-methyl-4-phenylpyridinium ion (MPP +)-induced apoptosis and oxidative stress in PC12 neuronal cells were investigated. PC12 cells treated with MPP + underwent apoptotic death as determined by MTT assay, flow cytometry and DNA agarose gel electrophoresis; intracellular accumulation of reactive oxygen species (ROS) was measured by DCFH-DA staining with laser scanning confocal microscopy (LSCM). Simultaneous treatment with tubuloside B markedly attenuated MPP +-induced cytotoxicity, DNA fragmentation, and intracellular accumulation of ROS. These results strongly indicate that tubuloside B prevents MPP +-induced apoptosis and oxidative stress. Tubuloside B may be applied as an antiparkinsonian agent.
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PMID:Tubuloside B from Cistanche salsa rescues the PC12 neuronal cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis and oxidative stress. 1245 84

Ginseng radix, the root of Panax ginseng C. A. MEYER (Araliaceae), is one of the best-known Oriental medicinal herbs with numerous therapeutic applications. To investigate whether Ginseng radix possesses a protective effect against 1-methyl-4-phenylpyridine (MPP(+))-induced cytotoxicity in neuronal cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, DNA fragmentation assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and caspase-3 enzyme assay were performed on PC12 neuronal cells. Cells treated with MPP(+) exhibited various apoptotic features, while cell pretreated with Ginseng radix prior to MPP(+) exposure showed a decrease in the occurrence of apoptotic features. These results suggest that Ginseng radix may exert a protective effect against MPP(+)-induced apoptosis in PC12 cells.
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PMID:Protective effect of aqueous extract of Ginseng radix against 1-methyl-4-phenylpyridinium-induced apoptosis in PC12 cells. 1464 68

In our study we investigated the neuroprotective effects of phenylethanoid glycosides (PhGs) from Cistanches salsa on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced apoptosis in cerebellar granule neurons (CGNs). CGNs were treated with 100 microM MPP(+) for 24h to induce apoptosis, simultaneously CGNs were incubated with PhGs at 10, 20 and 40 microg/ml, respectively. In addition CGNs were pretreated with PhGs at 20 microg/ml for 6, 12, 24 h, respectively, and then treated with 100 microM MPP(+) for 24 h. 3-(4,5-Dimethylthiazol-2-ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that the treatment of CGNs with PhGs inhibited the decrease of cell viability induced by MPP(+). The activation of caspase-3 and caspase-8 was induced by MPP(+) in apoptosis. The caspase-3 and caspase-8 fluorogenic assays showed that the treatments of CGNs with PhGs efficiently suppressed the activation of caspase-3 and caspase-8 induced by MPP(+). It is concluded that PhGs can prevent the MPP(+)-induced apoptosis in CGNs and exert its anti-apoptosis effect by inhibiting caspase-3 and caspase-8 activities.
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PMID:Phenylethanoid glycosides from Cistanches salsa inhibit apoptosis induced by 1-methyl-4-phenylpyridinium ion in neurons. 1565 76

The neuroprotective effects of catalpol, an iridoid glycoside present in the roots of Rehmannia glutinosa, on 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress in cultured mesencephalic neurons, especially dopaminergic neurons, were investigated. Exposure of mesencephalic neurons to 10microM MPP(+) induced a leakage of lactate dehydrogenase (LDH) and decreased cell viability, measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Catalpol increased neuron viability and markedly attenuated MPP(+)-induced dopaminergic neuron death in a dose-dependent manner. In order to clarify the neuroprotective mechanism of catalpol, mitochondrial function, the activities of endogenous antioxidants and the lipid peroxide content were measured. The results indicated that catalpol prevented the MPP(+)-induced inhibition of complex I activity and the loss of mitochondrial membrane potential. In addition, catalpol reduced the content of lipid peroxide and increased the activity of glutathione peroxidase and superoxide dismutase. Taken together, the above results suggest that catalpol may be a candidate drug for the treatment of oxidative stress-induced neurodegenerative disease.
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PMID:Neuroprotective effect of catalpol against MPP(+)-induced oxidative stress in mesencephalic neurons. 1751 20

The aim of the present study was to evaluate the neuroprotective effects of caffeine, an inhibitor of ataxia telangiectasia mutated (ATM) enzyme and an antagonist of adenosine receptors, in two models of apoptosis in cerebellar granule neurons (CGNs): the inhibition of mitochondrial complex I by the neurotoxin MPP(+) and serum and potassium deprivation. We used cerebellar granule neurons because of low glial contamination. Cell viability was measured by the MTT method, and apoptosis was evaluated by assessing DNA fragmentation with flow cytometry or quantification of nuclear condensation. Our data indicate that the neuroprotective effects of caffeine in the MPP+ model of apoptosis are mediated through activation of the ATM/p53 pathway. In addition, caffeine decreased the expression of cyclin D and the transcription factor E2F-1, a regulator of apoptosis in neurons. Caffeine-mediated neuroprotection was not mediated through blockade of adenosine receptors because DPCPX and CGS-15943, two antagonists of these receptors, failed to attenuate apoptosis produced by MPP+ treatment. In addition, caffeine did not exert neuroprotective effects after serum and potassium withdrawal, a p53-independent model of apoptosis. Taken together, our findings indicate that DNA damage/ATM activation is a key component of MPP+-induced apoptosis in CGNs through activation of p53 and reentry into the cell cycle, specifically expression of the transcription factor E2F-1.
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PMID:Neuroprotective effects of caffeine against complex I inhibition-induced apoptosis are mediated by inhibition of the Atm/p53/E2F-1 path in cerebellar granule neurons. 1763 2


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