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J Neurochem ; 92(5): 1021-32, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15715653

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.


Subject(s)
Dopamine/metabolism , Iron/toxicity , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Neurons/drug effects , Norepinephrine/pharmacology , Substantia Nigra/cytology , Adrenergic Uptake Inhibitors/pharmacology , Analysis of Variance , Animals , Catecholamine Plasma Membrane Transport Proteins , Cell Death/drug effects , Cells, Cultured , Chlorides/metabolism , Dicumarol/pharmacology , Dopamine Plasma Membrane Transport Proteins , Dopamine Uptake Inhibitors , Dose-Response Relationship, Drug , Electron Spin Resonance Spectroscopy/methods , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Ferric Compounds/metabolism , Ferric Compounds/pharmacology , Fluorescent Antibody Technique/methods , Imipramine/pharmacology , Indolequinones/pharmacology , Iron Isotopes/pharmacology , Membrane Glycoproteins/metabolism , Membrane Transport Proteins/metabolism , Microscopy, Confocal/methods , Models, Biological , Morpholines/pharmacology , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Nomifensine/pharmacology , Norepinephrine Plasma Membrane Transport Proteins , Rats , Rats, Inbred F344 , Rats, Wistar , Reboxetine , Serotonin Plasma Membrane Transport Proteins , Sodium/metabolism , Symporters/metabolism , Thiobarbituric Acid Reactive Substances/metabolism , Tyrosine 3-Monooxygenase/metabolism
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