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)

A number of studies have implicated the interactions of the excitatory amino acid L-glutamate (Glu) with its ionotropic and metabotropic receptors as important components of the mechanism underlying the dopaminergic neurotoxicity of 1-methyl-4-phenylpyridinium [MPP(+)]. Furthermore, microdialysis experiments have demonstrated that perfusion of relatively high concentrations of MPP(+) into the rat striatum evoke a delayed, massive release of Glu. Interestingly, perfusion of MPP(+) also mediates a similar release of glutathione (GSH). Together, these observations raise the possibility that the rise of extracellular Glu mediated by MPP(+) may be the result of hydrolysis of released GSH by gamma-glutamyl transpeptidase (gamma-GT). In the present investigation it is demonstrated that perfusions of solutions of 0.7 and 1.3 mM MPP(+) dissolved in artificial cerebrospinal fluid into the rat striatum evoke neurotoxic damage to dopaminergic terminals, assessed by both a two-day test/challenge procedure and tyrosine hydroxylase immunoreactivity, but without the release of Glu. Perfusions of 2.5 mM MPP(+) cause more extensive dopaminergic neurotoxicity and a dose-dependent release of Glu. However, neither this release of Glu nor MPP(+)-induced dopaminergic neurotoxicity are blocked by the irreversible gamma-GT inhibitor acivicin. Together, these observations indicate that a rise of extracellular levels of Glu is not essential for the dopaminergic neurotoxicity of MPP(+). Furthermore, the rise of extracellular Glu caused by perfusion of 2.5 mM MPP(+) is not the result of the gamma-GT-mediated hydrolysis of released GSH. It is possible that the rise of extracellular levels of Glu, L-aspartate, L-glycine and L-taurine evoked by perfusions of 2.5 mM MPP(+) into the rat striatum may reflect, at least in part, the release of these amino acids from astrocytes.
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PMID:Increased extracellular glutamate evoked by 1-methyl-4-phenylpyridinium [MPP(+)] in the rat striatum is not essential for dopaminergic neurotoxicity and is not derived from released glutathione. 1617 62

The effect of alkaloid piperine against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated PC12 cells was assessed. Piperine treatment revealed a differential effect on the cytotoxicity of MPP(+) and had its maximum inhibitory effect at 1 microM. The addition of piperine (0.5-10 microM) significantly reduced the MPP(+)-induced nuclear damage, mitochondrial membrane permeability changes, formation of reactive oxygen species and depletion of GSH. In contrast, piperine at 50-100 microM showed cytotoxicity and exhibited an additive effect against the MPP(+) toxicity. The results indicate that piperine had a differential effect on the cytotoxicity of MPP(+) depending on concentration. Piperine at low concentrations may reduce the MPP(+)-induced viability loss in PC12 cells by suppressing the changes in the mitochondrial membrane permeability, leading to the release of cytochrome c and subsequent activation of caspase-3. The effects may be ascribed to its inhibitory action on the formation of reactive oxygen species and depletion of GSH.
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PMID:Piperine inhibition of 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells. 1662 79

Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The aim of the present study was to assess the influence of the mitochondrial membrane permeability transition inhibition against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) and 6-hydroxydopamine (6-OHDA) in relation to the mitochondria-mediated cell death process and role of oxidative stress. Both MPP(+) and 6-OHDA induced the nuclear damage, the changes in the mitochondrial membrane permeability, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species and the depletion of GSH in differentiated PC12 cells. Cyclosporin A (CsA), trifluoperazine and aristolochic acid, inhibitors of mitochondrial permeability transition, significantly attenuated the MPP(+)-induced mitochondrial damage leading to caspase-3 activation, increased oxidative stress and cell death. In contrast to MPP(+), the cytotoxicity of 6-OHDA was not reduced by the addition of the mitochondrial permeability transition inhibitors. The results show that the cytotoxicity of MPP(+) may be mediated by the mitochondrial permeability transition formation, which is associated with formation of reactive oxygen species and the depletion of GSH. In contrast, the 6-OHDA-induced cell injury appears to be mediated by increased oxidative stress without intervention of the mitochondrial membrane permeability transition.
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PMID:Differential involvement of mitochondrial permeability transition in cytotoxicity of 1-methyl-4-phenylpyridinium and 6-hydroxydopamine. 1662 21

The present study investigated the promoting effect of oxysterol 7-ketocholesterol against the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated PC12 cells. 7-Ketocholesterol significantly enhanced the MPP(+)-induced nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species and depletion of GSH. N-Acetylcysteine, ascorbate, trolox, carboxy-PTIO and Mn-TBAP reduced the cytotoxic effect of MPP(+) in the presence of 7-ketocholesterol. The results indicate that 7-ketocholesterol shows a synergistic effect against the cytotoxic effect of MPP(+). 7-Ketocholesterol may enhance the MPP(+)-induced viability loss in PC12 cells by promoting the mitochondrial membrane permeability change, release of cytochrome c and subsequent activation of caspase-3, which is associated with the increased formation of reactive oxygen species and depletion of GSH. The findings suggest that 7-ketocholesterol as a promoting agent for the formation of mitochondrial permeability transition may enhance the toxic neuronal cell injury.
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PMID:7-Ketocholesterol enhances 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells. 1671 9

Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The effect of econazole against the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated PC12 cells was assessed in relation to the mitochondrial membrane permeability changes. Treatment of PC12 cells with MPP(+) resulted in the nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species (ROS) and depletion of GSH. Econazole (0.25-2.5 microM) inhibited the cytotoxicity of MPP(+) or rotenone. The addition of econazole (0.5 microM) significantly attenuated the MPP(+)-induced mitochondrial damage, elevation of intracellular Ca(2+) level and cell death. However, because of the cytotoxicity, econazole at 5 microM did not attenuate the toxicity of MPP(+). The results show that econazole at the low concentrations may reduce the MPP(+)-induced viability loss in PC12 cells by suppressing the mitochondrial permeability transition, leading to activation of caspase-3 and the elevation of intracellular Ca(2+) levels, which are associated with the increased formation of ROS and depletion of GSH.
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PMID:Econazole attenuates cytotoxicity of 1-methyl-4-phenylpyridinium by suppressing mitochondrial membrane permeability transition. 1671 39

1-Methyl-4-phenylpyridinium (MPP(+)) or 6-hydroxydopamine (6-OHDA) caused a nuclear damage, the mitochondrial membrane permeability changes, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species and the depletion of GSH in PC12 cells. Nicardipine (a calcium channel blocker), EGTA (an extracellular calcium chelator), BAPTA-AM (a cell permeable calcium chelator) and calmodulin antagonists (W-7 and calmidazolium) attenuated the MPP(+)-induced mitochondrial damage and cell death. In contrast, the compounds did not reduce the toxicity of 6-OHDA. Treatment with MPP(+ )or 6-OHDA evoked the elevation of intracellular Ca(2+) levels. Unlike cell injury, addition of nicardipine, BAPTA-AM and calmodulin antagonists prevented the elevation of intracellular Ca(2+) levels due to both toxins. The results show that the MPP(+)-induced formation of the mitochondrial permeability transition seems to be mediated by elevation of intracellular Ca(2+) levels and calmodulin action. In contrast, the 6-OHDA-induced cell death seems to be mediated by Ca(2+)-independent manner.
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PMID:Differential involvement of intracellular Ca2+ in 1-methyl-4-phenylpyridinium- or 6-hydroxydopamine-induced cell viability loss in PC12 cells. 1680 60

Protocatechuic acid (PCA), a phenolic compound isolated from the kernels of Alpinia (A.) oxyphylla, showed antioxidant neuroprotective effect in our previous study. Here, we investigated the effect of PCA on the MPP(+)-induced mitochondrial dysfunction and apoptotic cell death in PC12 cells. The apoptosis in MPP(+)-induced PC12 cells was associated with loss of mitochondrial membrane potential, the formation of reactive oxygen species (ROS), GSH depletion, activation of caspase-3 and down-regulation of Bcl-2. In contrast, treatment of PC12 cells with PCA significantly prevented the above-mentioned mitochondrial dysfunction. Our data pointed to the potential clinical application/use of PCA to overcome neurodegenerative diseases such as Parkinson's disease.
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PMID:Protocatechuic acid suppresses MPP+ -induced mitochondrial dysfunction and apoptotic cell death in PC12 cells. 1680 28

The present study investigated the effect of 5-hydroxydecanoate, a selective mitochondrial K(ATP) channel blocker, on the cytotoxicity of neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated PC12 cells. 5-Hydroxydecanoate and glibenclamide (a cell surface and mitochondrial K(ATP) channel inhibitor) reduced the MPP(+)-induced cell death and GSH depletion and showed a maximal inhibitory effect at 5 and 10 microM, respectively. Addition of 5-hydroxydecanoate attenuated the MPP(+)-induced nuclear damage, changes in the mitochondrial membrane permeability and increase in the reactive oxygen species formation in PC12 cells. The results show that 5-hydroxydecanote may prevent the MPP(+)-induced viability loss in PC12 cells by suppressing formation of the mitochondrial permeability transition, leading to the cytochrome c release and caspase-3 activation. This effect appears to be accomplished by the inhibitory action on the formation of reactive oxygen species and the depletion of GSH. The blockade of mitochondrial K(ATP) channels seems to prevent the MPP(+)-induced neuronal cell damage.
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PMID:Modulation of 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells by K(ATP) channel block. 1710 75

Decreased glutathione levels associated with increased oxidative stress are a hallmark of numerous neurodegenerative diseases, including Parkinson's disease. GSH is an important molecule that serves as an anti-oxidant and is also a major determinant of cellular redox environment. Previous studies have demonstrated that neurotoxins can cause changes in reduced and oxidized GSH levels; however, information regarding steady state levels remains unexplored. The goal of this study was to characterize changes in cellular GSH levels and its regulatory enzymes in a dopaminergic cell line (N27) following treatment with the Parkinsonian toxin, 1-methyl-4-phenylpyridinium (MPP(+)). Cellular GSH levels were initially significantly decreased 12 h after treatment, but subsequently recovered to values greater than controls by 24 h. However, oxidized glutathione (GSSG) levels were increased 24 h following treatment, concomitant with a decrease in GSH/GSSG ratio prior to cell death. In accordance with these changes, ROS levels were also increased, confirming the presence of oxidative stress. Decreased enzymatic activities of glutathione reductase and glutamate-cysteine ligase by 20-25% were observed at early time points and partly account for changes in GSH levels after MPP(+) exposure. Additionally, glutathione peroxidase activity was increased 24 h following treatment. MPP(+) treatment was not associated with increased efflux of glutathione to the medium. These data further elucidate the mechanisms underlying GSH depletion in response to the Parkinsonian toxin, MPP(+).
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PMID:1-methyl-4-phenylpyridinium-induced alterations of glutathione status in immortalized rat dopaminergic neurons. 1739 26

Inhibition of astrocytic apoptosis has been regarded as a novel prospective strategy for treating neurodegenerative disorders such as Parkinson's disease. In the present study, we demonstrated that iptakalim (IPT), an ATP-sensitive potassium channel (K(ATP) channel) opener, exerted protective effect on MPP(+)-induced astrocytic apoptosis, which was reversed by selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate. Further study revealed that IPT inhibited glutathione (GSH) depletion, mitochondrial membrane potential loss and subsequent release of pro-apoptotic factors (cytochrome c and apoptosis-inducing factor (AIF), and c-Jun NH(2)-terminal kinase/mitogen-activated protein kinases (MAPK) phosphorylation induced by MPP(+). Meanwhile, extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 inhibited the protective effect of IPT on MPP(+)-induced astrocytic apoptosis. Furthermore, IPT could also activate ERK/MAPK and maintain increased phospho-ERK1/2 level after MPP(+) exposure. Taken together, these findings reveal for the first time that IPT protects against MPP(+)-induced astrocytic apoptosis via inhibition of mitochondria apoptotic pathway and regulating the MAPK signal transduction pathways by opening mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels in astrocytes. And targeting K(ATP) channels expressed in astrocytes may provide a novel therapeutic strategy for neurodegenerative disorders.
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PMID:ATP-sensitive potassium channel opener iptakalim protects against MPP-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. 1763 69


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