Neurotoxic relationship between dopamine and iron in the striatal dopaminergic nerve terminals

The neurotoxic effect of dopamine (DA) and iron(III) on DAergic terminals i n striatum has been studied by intracerebral microdialysis technique. Twent y-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 st riatal DAergic terminals, supported by tyrosine hydroxylase immunohistochem istry technique. Perfusion of exogenous DA, as well as iron(III) 10 and 100 mu M, did not produce any neurotoxic effect. However, perfusion of iron(II I) (333 and 1000 mu M) produced a concentration-dependent toxic effect. Co- perfusion of iron(III) at non-toxic concentration (100 mu M) with DA (15 mu M) produced a toxic effect. Elevation of the endogenous extracellular leve ls of DA by inhibiting its uptake with nomifensine increased the neurotoxic effect of iron(III) in a dose-dependent manner. The use of tetrodotoxin af ter elevation of DA with nomifensine partially prevented the neurotoxic eff ect of its co-perfusion with iron(III) (100 mu M). These results suggest th at DAergic system could be synergistically damaged by DA and iron(III). Thu s, alterations in the clearance of DA from extracellular space along with a n increase of iron may have significant consequences for DAergic system tox icity. (C) 2000 Elsevier Science B.V. All rights reserved.