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Monoamine transporter inhibitors and norepinephrine reduce dopamine‐dependent iron toxicity in cells derived from the substantia nigra
Author(s) -
Paris Irmgard,
MartinezAlvarado Pedro,
PerezPastene Carolina,
Vieira Marcelo N. N.,
OleaAzar Claudio,
RaismanVozari Rita,
Cardenas Sergio,
Graumann Rebeca,
Caviedes Pablo,
SeguraAguilar Juan
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02931.x
Subject(s) - nomifensine , dopamine , norepinephrine , chemistry , catecholamine , dopamine transporter , endocrinology , monoamine neurotransmitter , medicine , norepinephrine transporter , monoamine oxidase , pharmacology , dopamine uptake inhibitors , dopaminergic , serotonin , biology , biochemistry , enzyme , receptor
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 µ m 59 FeCl 3 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 µ m nomifensine (43% p < 0.05), 100 µ m imipramine (62% p < 0.01), 30 µ m reboxetine (71% p < 0.01) and 2 m m dopamine (84% p < 0.01). The uptake of 59 Fe–dopamine complex was Na + , Cl – and temperature dependent. No toxic effects in RCSN‐3 cells were observed when the cells were incubated with 100 µ m FeCl 3 alone or complexed with dopamine. However, 100 µ m Fe(III)–dopamine in the presence of 100 µ m dicoumarol, an inhibitor of DT‐diaphorase, induced toxicity (44% cell death; p < 0.001), which was inhibited by 2 µ m nomifensine, 30 µ m reboxetine and 2 m m norepinephrine. The neuroprotective action of norepinephrine can be explained by (1) its ability to form complexes with Fe 3+ , (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.