Using energy-dispersive x-ray analysis on an electron microscope working in the scanning transmission electron microscopy mode equipped with a microanalysis system, we studied the subcellular distribution of trace elements in neuromelanin-containing neurons of the substantia nigra zona compacta (SNZC) of three cases of idiopathic Parkinson's disease (PD) [one with Alzheimer's disease (AD)] and of three controls, in Lewy bodies of SNZC, and in synthetic dopamine-melanin chemically charged or uncharged with Fe. Weak but significant Fe peaks similar to those of a synthetic melanin-Fe3+ complex were seen only in intraneuronal highly electron-dense neuromelanin granules of SNZC cells of PD brains, with the highest levels in a case of PD plus AD, whereas a synthetic melanin-Fe2+ complex showed much lower iron peaks, indicating that neuromelanin has higher affinity for Fe3+ than for Fe2+. No detectable Fe was seen in nonmelanized cytoplasm of SNZC neurons and in the adjacent neuropil in both PD and controls, in Lewy bodies in SNZC neurons in PD, and in synthetic dopamine-melanin uncharged with iron. These findings, demonstrating for the first time a neuromelanin-iron complex in dopaminergic SNZC neurons in PD, support the assumption that an iron-melanin interaction contributes significantly to dopaminergic neurodegeneration in PD and PD plus AD.

The reactions of dopamine (1-amino-2-(3,4-dihydroxyphenyl)-ethane, DA), 5-hydroxydopamine (5-OHDA), and 6-hydroxydopamine (6-OHDA), with molecular oxygen-with and without the addition of catalytic amounts of iron(III) and other metal ions-have been studied and the implication of these results with respect to the chemistry involved in the progress of Parkinson's disease is discussed. In the presence of O2 DA reacts spontaneously without the necessity of metal-ion catalysis under the production of stoichiometric amounts of H2O2, to form initially pink dopaminochrome, which is not stable and reacts further (without the consumption of dioxygen) to form the insoluble polymeric material known as 'melanine'. DA reacts with iron(III) yielding an intermediate 1:1 complex, which decomposes releasing Fe(II) and the semiquinone, which reacts further under involvement of both Fe(III) and dioxygen. 6-OHDA reacts without showing the necessity of such an intermediate, and it is shown to be able to release iron as Fe(II) from ferritine. On the other hand, it is shown (in vitro) that Fe(II) reacts in a Fenton type reaction with DA and the present H2O2 producing 5-OHDA and especially 6-OHDA. Based on these mutual interacting reactions a mechanism for the initiation and progress of Parkinson's disease is suggested. The catalytic effects of some other transition-metal ions are presented and an explanation for the peculiarly toxic effects of manganese(II) is put forward. Finally, a possible reason for the effect that nicotine has in the mitigation of Parkinson's disease is discussed.

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