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  • 1
    Electronic Resource
    Electronic Resource
    Mitochondrial Mechanisms of Neurotoxicity (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 648 (1992), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1992.tb24521.x
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  • 2
    Electronic Resource
    Electronic Resource
    Effects of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine and Related Compounds on the Uptake of [3H]3,4-Dihydroxyphenylethylamine and [3H]5-Hydroxytryptamine in Neostriatal Synaptosomal Preparations (1985)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 44 (1985), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is known to cause a destruction of the dopaminergic nigrostriatal pathway in certain animal species including mice. MPTP and some structurally related analogs were tested in vitro for their capacity to inhibit the uptake of [3H]3,4-dihydroxyphenylethylamine-([3H]DA), [3H]5-hydroxytryptamine ([3H]5-HT), and [3H]γ-aminobutyric acid ([3H]GABA) in mouse neostriatal synaptosomal preparations. MPTP was a very potent inhibitor of [3H]5-HT uptake (IC50 value 0.14 μM), a moderate inhibitor of [3H]DA uptake (IC50 value 2.6 μM), and a very weak inhibitor of [3H]GABA uptake (no significant inhibition observed at 10 μM MPTP). In other experiments, MPTP caused some release of previously accumulated [3H]DA and [3H]5-HT, but in each case MPTP was considerably better as an uptake inhibitor than as a releasing agent. The 4-electron oxidation product of MPTP, i.e., 1-methyl-4-phenyl-pyridinium iodide (MPP+), was a very potent inhibitor of [3H]DA uptake (IC50 value 0.45 μM) and of [3H]5-HT uptake (IC50 value 0.78 μM) but MPP+ was a very weak inhibitor of [3H]GABA uptake. These data may have relevance to the neurotoxic actions of MPTP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1985.tb07146.x
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  • 3
    Electronic Resource
    Electronic Resource
    Inhibitory Effects of Ascorbic Acid on the Binding of [3H]Dopamine Antagonists to Neostriatal Membrane Preparations : Relationship to Lipid Peroxidation (1982)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 38 (1982), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Ascorbic acid, sodium ascorbate, and isoascorbic acid (the stereo-isomer of ascorbic acid) inhibited the stereospecific binding of [3H]spiroperidol to neostriatal membrane preparations. Greater inhibitory effects were obtained at intermediate concentrations of the three ascorbic acid analogs (i.e., 0.06 and 0.6 mM) than at higher (6 mM) or lower (0.006 mM) concentrations. In parallel experiments, the three ascorbic acid analogs induced lipid peroxidation, which was also greater at the two intermediate than at higher or lower concentrations. Several known inhibitors of lipid peroxidation, including propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, α-naphthol, and cobalt chloride, as well as the iron chelating agents EDTA and DETAPAC (diethylenetriaminepentaacetic acid) were able to counteract the effects of the ascorbic acid analogs on both lipid peroxidation and on [3H]spiroperidol binding. These data strongly suggest that an iron-catalyzed lipid peroxidation is responsible for the observed inhibitory effects on binding. In other experiments, neostriatal membrane preparations that were preincubated with ascorbic acid (0.6 mM) and subsequently washed still had greatly diminished capacity to bind [3H]spiroperidol, indicating that ascorbic acid need not be physically present during the binding assay in order to affect binding. This experimental procedure also appears to be a way in which [3H]spiroperidol binding sites can be inactivated and washed free of the inactivating agent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1982.tb05341.x
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  • 4
    Electronic Resource
    Electronic Resource
    1-Methyl-4-(2′-Ethylphenyl)-1,2,3,6-Tetrahydropyridine- Induced Toxicity in PC12 Cells Is Enhanced by Preventing Glycolysis (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 58 (1992), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The effects of l-methyl-4-(2′-ethylphenyl)-1,2,3,6-tetrahydropyridine (2′Et-MPTP), l-methyl-4-(2′-ethyl-phenyl)pyridinium (2′Et-MPP+), and the classic complex 1 inhibitor, rotenone, on toxicity as well as on rates of glucose use and lactate production were studied using the pheochro-mocytoma PC12 cell line. PC12 cells are neoplastic in nature and have a high rate of glycolysis accompanied by a large production of lactate and a low use of glucose carbon through the Krebs cycle. l-Methyl-4-phenylpyridinium (MPP+) and analogues such as 2′Et-MPP+ are actively accumulated by mitochondrial preparations in vitro and block NADH de-hydrogenase of complex 1. This blockade results in biochemical sequelae that are ultimately cytotoxic. In this study, untreated PC12 cells used glucose and concomitantly accumulated lactate in a time-dependent manner at all concentrations of glucose studied. Treatment with 50 pM 2′Et-MPP+ or 50 nAf rotenone increased both rates significantly, indicating a shift toward increased glycolysis. Cell death caused by the neurotoxins was also time and concentration dependent and markedly enhanced by glucose depletion in the medium. The increase in 2′Et-MPTP-induced toxicity in low glucose-supplemented cells was not due to an increase in pyridinium formation from the tetrahydro-pyridine, but rather to the lack of glucose for glycolysis. Moreover, inhibition of glycolysis with 2-deoxyglucose or io-doacetic acid also enhanced the lethality of the neurotoxins to the cells. The data in this study provide additional support to the hypothesis that 2′Et-MPP+ or related analogues act to kill cells by inhibiting mitochondrial respiration. Furthermore, these findings support the hypothesis that the ability of 2′Et-MPTP or its analogues to induce toxicity is dependent on the relative contributions of glycolysis and mitochondrial oxidation to the energy needs of a particular cell or model system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1992.tb09361.x
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  • 5
    Electronic Resource
    Electronic Resource
    1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine- and 1-Methyl-4-(2′-Ethylphenyl)-1,2,3,6-Tetrahydropyridine-Induced Toxicity in PC 12 Cells: Role of Monoamine Oxidase A (1990)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 55 (1990), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The toxicity of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), l-methyl-4-(2′-ethylphenyl)-1,2,3,6-tetrahydropyridine (2'Et-MPTP), and their corresponding pyridinium species was studied in the rat pheochromocytoma PC 12 cell line. MPTP and its analogues are known to be metabolized by monoamine oxidase (MAO) to dihydropyr-idinium intermediates which are further transformed, either enzymatically or spontaneously, into pyridinium species. MAO activity in PC12 cells is almost exclusively of the A form, and 2'Et-MPTP is a good substrate for both MAO-A and MAO-B. In contrast, MPTP is a poor substrate for MAO-A, but a good substrate for MAO-B. 2'Et-MPTP caused considerably more cell death than MPTP in the PC 12 cells. However, l-methyl-4–(2′-ethylphenyl)pyridinium and 1-methyl-4-phenylpyridinium, the corresponding pyridinium species formed from 2'Et-MPTP and MPTP, respectively, were equipotent as toxins. The toxic effects of the tetrahy-dropyridines and their corresponding pyridiniums were both concentration- and time-dependent. Measurements of the levels of the pyridinium species formed and the remaining tetrahydropyridine in the media indicated that 2'Et-MPTP was converted about five to seven times more readily into its toxic pyridinium species than was MPTP. There was, moreover, an excellent correlation between amount of pyridinium formed and cell death. There was also a parallel between the capacity of clorgyline and pargyline, irreversible MAO inhibitors, to decrease the formation of the pyridinium species and their capacity to protect against the toxic actions of the tetrahydropyridines. These data are consistent with the concept that the MAO-A-dependent formation of the pyridinium species from the tetrahydropyridine is a prerequisite for toxicity in PC12 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1990.tb04572.x
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  • 6
    Electronic Resource
    Electronic Resource
    Studies on the Oxidation of the Dopaminergic Neurotoxin 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine by Monoamine Oxidase B (1985)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 45 (1985), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: 1-Methyl-4-phenyl- 1,2,5,6 -tetrahydropyridine (MPTP) is a chemical that, after injection into experimental animals, including mice and monkeys, causes a degeneration of the nigrostriatal pathway. We carried out experiments designed to study the in vitro oxidation of MPTP by mouse brain mitochondrial preparations. MPTP was actively oxidized by the mitochondrial preparations, with Km and Vmax values very similar to those of benzyl amine, a typical substrate for MAO-B. MPTP was oxidized considerably better than many of its analogs, even those with relatively minor structural changes. Several monoamine oxidase inhibitors (MAOI) were potent inhibitors of MPTP oxidation, and there was a highly significant correlation between the capacity of the MAOI tested to inhibit MPTP oxidation and benzylamine oxidation. There was no correlation between the capacity of the MAOI to inhibit MPTP oxidation and their capacity to inhibit the oxidation of tryptamine, a substrate for MAO-A. In other experiments, MPTP was an excellent substrate for pure MAO-B, prepared from bovine liver. All of these data. combined with the fact that MAO-B inhibitors can protect against MPTP-induced dopami nergic neurotoxicity in vivo. point to an important role for MAO-B in MPTP metabolism in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1985.tb05522.x
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  • 7
    Electronic Resource
    Electronic Resource
    Oxidation of Analogs of l-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine by Monoamine Oxidases A and B and the Inhibition of Monoamine Oxidases by the Oxidation Products (1989)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 53 (1989), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Twenty analogs of l-methyl-4-phenyl-l,2,3,6-tet-rahydropyridine (MPTP) were tested for their capacity to be xidized by pure monoamine oxidase-A (MAO-A) prepared from human placenta and pure monoamine oxidase-B (MAO-B) prepared from beef liver. Several of the MPTP analogs were very good substrates for MAO-A, for MAO-B, or for both and had low Km values and high turnover numbers. These values were similar to or even better than those of kynuramine and benzylamine, good substrates for MAO-A and MAO-B, respectively. MPTP had relatively low Km values for oxidation by both MAO-A and MAO-B. In contrast, the turnover number for MPTP oxidation by MAO-B was considerably higher than the value for MAO-A. The corresponding pyridinium species of MPTP and several of the MPTP analogs inhibited MAO-A competitively with Ki values at micromolar concentrations; in contrast the pyridinium species inhibited MAO-B competitively at considerably higher concentrations (i.e., 100 μM or greater Ki values). The data provide information concerning the structural requirements for the oxidation of tetrahydropyridines by MAO-A and MAO-B and the inhibition of these enzymes by pyridini-ums
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1989.tb09250.x
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  • 8
    Electronic Resource
    Electronic Resource
    Prevention of the Nigrostriatal Toxicity of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine by Inhibitors of 3,4-Dihydroxyphenylethylamine Transport (1986)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 47 (1986), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract The 3,4-dihydroxyphenylethylamine (DA, dopamine) uptake inhibitors GBR 13,069, amfonelic acid, WIN-35,065-2, WIN-35,428, nomifensine, mazindol, cocaine, McN-5908, McN-5847, and McN-5292 were effective in preventing [3H]DA and [3H]l-methyl-4-phenylpyridinium (MPP+) uptake in rat and mouse neostriatal tissue slices. These DA uptake inhibitors also were effective in attenuating the MPP+-induced release of [3H]DA in vitro. 1-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) administration to mice (6 ± 25 mg/kg i.p.) resulted in a large (70–80%) decrement in neostriatal DA. WIN-35,428 (5 mg/kg), GBR 13,069 (10 mg/kg), McN-5292 (5 mg/kg), McN-5908 (2 mg/ kg), and amfonelic acid (2 mg/kg), when administered intraperitoneally 30 min prior to each MPTP injection, fully protected against MPTP-induced neostriatal damage. Other DA uptake inhibitors showed partial protection in vivo at the doses selected. Desmethylimipramine did not prevent [3H]MPP+ uptake or MPP+-induced release of [3H]DA in vitro, and did not protect against MPTP neurotoxicity in vivo. These results support the hypothesis put forth previously by others that the active uptake of MPP+ by dopaminergic neurons is necessary for toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1986.tb00722.x
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  • 9
    Electronic Resource
    Electronic Resource
    Ascorbate-Induced Lipid Peroxidation and Inhibition of [3H]Spiroperidol Binding in Neostriatal Membrane Preparations (1983)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 41 (1983), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Sodium ascorbate caused an increased lipid peroxidation and a large decrement in [3H]spiroperidol binding in a rat neostriatal membrane preparation (preparation C). Both effects were greater at intermediate (0.05 and 0.5 mM) than at higher or lower ascorbate concentrations. In contrast, in another neostriatal membrane preparation (preparation A), there was no loss of [3H]spiroperidol binding and only a small increase in lipid peroxidation caused by ascorbate. However, both the ascorbate-induced increase in lipid peroxidation and loss of [3H]spiroperidol binding were greatly enhanced in preparation A by the addition of iron salts. In experiments designed to explore reasons for these apparent discrepancies, we discovered that the method of tissue preparation was a critical factor. The ascorbate effects were consistently greater in a tissue preparation which was originally homogenized in an isotonic sucrose medium and centrifuged, and the cell debris discarded (as was done in preparation C), than in one in which the tissue was homogenized in a hypotonic medium and in which no low-speed centrifugation was done (as was done in preparation A). In other experiments, of several cations tested, only ferrous and ferric potentiated the above-described effects of ascorbate. Some ascorbic acid derivatives (e.g., isoascorbic acid) had properties similar to those of ascorbic acid, whereas several reducing agents could, in the presence of added iron salts, cause both a lipid peroxidation and a loss of [3H]spiroperidoI binding. However, the other reducing agents tested (e.g., dithiothreitol) were iess potent in both regards than was ascorbate. In other experiments, several chelating agents (e.g., EDTA) or commonly used inhibitors of lipid peroxidation (e.g., propyl gallate) were able to counteract the effects of ascorbate on lipid peroxidation and on [3H]spiroperidol binding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1983.tb00836.x
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  • 10
    Electronic Resource
    Electronic Resource
    Hydrogen Peroxide Production by Rat Brain In Vivo (1980)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 34 (1980), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: H2 O2 production by rat brain in vivo was observed with a method based on the measurement of brain catalase. The administration to the rat of 3-amino-1, 2, 4-triazole, an H2 O2- dependent inhibitor of catalase, caused progressive inhibition of brain catalase activity in both the supernatant and pellet fractions of homogenates of the striatum and prefrontal cortex. The prevention of catalase inhibition by prior administration of ethanol confirmed that catalase inhibition in vivo was dependent upon H2 O2. A significant portion of the catalase (30-33%) appeared in the supernatant fraction from a slow-speed homogenization procedure and was not significantly contaminated by either erythrocytes or capillaries. In the whole homogenate, less than 6% of the catalase activity was attributed to erythrocytes. Modification of intracellular monoamine oxidase activity by either pargyline or reserpine did not change the rate of inhibition of catalase by aminotriazole. A probable interpretation of these data is that H2 O2 generated by mitochondrial monoamine oxidase does not reach the catalase compartment; the catalase is contained in particles described by other investigators as the microperoxisomes of brain. In studies in vitro, the production of H2 O2 by rat brain mitochondria with either dopamine or serotonin as substrate was confirmed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1980.tb11222.x
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