Abstract
The role of dopamine in iron uptake into catecholaminergic neurons, and dopamine oxidation to aminochrome and its one-electron reduction in iron-mediated neurotoxicity, was studied in RCSN-3 cells, which express both tyrosine hydroxylase and monoamine transporters. The mean +/- SD uptake of 100 microm 59FeCl3 in RCSN-3 cells was 25 +/- 4 pmol per min per mg, which increased to 28 +/- 8 pmol per min per mg when complexed with dopamine (Fe(III)-dopamine). This uptake was inhibited by 2 microm nomifensine (43%p < 0.05), 100 microm imipramine (62%p < 0.01), 30 microm reboxetine (71%p < 0.01) and 2 mm dopamine (84%p < 0.01). The uptake of 59Fe-dopamine complex was Na+, Cl- and temperature dependent. No toxic effects in RCSN-3 cells were observed when the cells were incubated with 100 microm FeCl3 alone or complexed with dopamine. However, 100 microm Fe(III)-dopamine in the presence of 100 microm dicoumarol, an inhibitor of DT-diaphorase, induced toxicity (44% cell death; p < 0.001), which was inhibited by 2 microm nomifensine, 30 microm reboxetine and 2 mm norepinephrine. The neuroprotective action of norepinephrine can be explained by (1) its ability to form complexes with Fe3+, (2) the uptake of Fe-norepinephrine complex via the norepinephrine transporter and (3) lack of toxicity of the Fe-norepinephrine complex even when DT-diaphorase is inhibited. These results support the proposed neuroprotective role of DT-diaphorase and norepinephrine.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic Uptake Inhibitors / pharmacology
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Analysis of Variance
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Animals
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Catecholamine Plasma Membrane Transport Proteins
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Cell Death / drug effects
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Cells, Cultured
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Chlorides / metabolism
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Dicumarol / pharmacology
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Dopamine / metabolism*
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors
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Dose-Response Relationship, Drug
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Electron Spin Resonance Spectroscopy / methods
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Embryo, Mammalian
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Enzyme Inhibitors / pharmacology
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Ferric Compounds / metabolism
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Ferric Compounds / pharmacology
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Fluorescent Antibody Technique / methods
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Imipramine / pharmacology
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Indolequinones / pharmacology
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Iron / toxicity*
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Iron Isotopes / pharmacology
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Membrane Glycoproteins / metabolism
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Membrane Transport Modulators*
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Membrane Transport Proteins / antagonists & inhibitors*
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Membrane Transport Proteins / metabolism
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Microscopy, Confocal / methods
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Models, Biological
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Morpholines / pharmacology
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects*
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Neurons / metabolism
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Nomifensine / pharmacology
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Norepinephrine / pharmacology*
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Norepinephrine Plasma Membrane Transport Proteins
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Rats
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Rats, Inbred F344
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Rats, Wistar
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Reboxetine
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Serotonin Plasma Membrane Transport Proteins
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Sodium / metabolism
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Substantia Nigra / cytology*
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Symporters / metabolism
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Thiobarbituric Acid Reactive Substances / metabolism
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Adrenergic Uptake Inhibitors
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Catecholamine Plasma Membrane Transport Proteins
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Chlorides
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors
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Enzyme Inhibitors
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Ferric Compounds
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Indolequinones
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Iron Isotopes
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Membrane Glycoproteins
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Membrane Transport Modulators
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Membrane Transport Proteins
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Morpholines
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Nerve Tissue Proteins
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Norepinephrine Plasma Membrane Transport Proteins
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Serotonin Plasma Membrane Transport Proteins
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Slc22a1 protein, rat
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Slc6a2 protein, rat
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Slc6a4 protein, rat
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Symporters
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Thiobarbituric Acid Reactive Substances
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Nomifensine
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aminochrome 1
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Dicumarol
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Reboxetine
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Sodium
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Iron
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Tyrosine 3-Monooxygenase
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Imipramine
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Dopamine
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Norepinephrine