Neurotoxic relationship between dopamine and iron in the striatal dopaminergic nerve terminals.
The neurotoxic effect of dopamine (DA) and iron(III) on DAergic terminals in striatum has been studied by intracerebral microdialysis technique. Twenty-four hours after surgery (day 1), DA and/or iron(III) with and without DA reuptake inhibitor, nomifensine, were perfused for 1 h. Forty-eight hours after surgery (day 2), MPP(+) 1 mM was perfused for 15 min and the output of DA was measured, its amount being directly proportional to the remaining striatal DAergic terminals, supported by tyrosine hydroxylase immunohistochemistry technique. Perfusion of exogenous DA, as well as iron(III) 10 and 100 microM, did not produce any neurotoxic effect. However, perfusion of iron(III) (333 and 1000 microM) produced a concentration-dependent toxic effect. Co-perfusion of iron(III) at non-toxic concentration (100 microM) with DA (15 microM) produced a toxic effect. Elevation of the endogenous extracellular levels of DA by inhibiting its uptake with nomifensine increased the neurotoxic effect of iron(III) in a dose-dependent manner. The use of tetrodotoxin after elevation of DA with nomifensine partially prevented the neurotoxic effect of its co-perfusion with iron(III) (100 microM). These results suggest that DAergic system could be synergistically damaged by DA and iron(III). Thus, alterations in the clearance of DA from extracellular space along with an increase of iron may have significant consequences for DAergic system toxicity.
Santiago
M
M
Departamento de Bioquímica, Bromatología y Toxicología, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain.
Matarredona
E R
ER
Granero
L
L
Cano
J
J
Machado
A
A
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004298:Dopamine / Q000008:administration & dosage / Q000032:analysis / Q000096:biosynthesis / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D007150:Immunohistochemistry; D007501:Iron / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D017551:Microdialysis; D009627:Nomifensine / Q000494:pharmacology; D010477:Perfusion; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D009627:Nomifensine; D013779:Tetrodotoxin; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine