Iron-Mediated Generation of the Neurotoxin 6-Hydroxydopamine Quinone by Reaction of Fatty Acid Hydroperoxides with Dopamine:  A Possible Contributory Mechanism for Neuronal Degeneration in Parkinson's Disease

Abstract

Exposure of dopamine to an excess of linoleic acid 13-hydroperoxide (13-hydroperoxyoctadecadienoic acid) in the presence of ferrous ions in Tris buffer, pH 7.4, resulted in a relatively fast, oxygen-independent reaction exhibiting first-order kinetics with respect to both catecholamine and metal concentrations. Product analysis in the early stages revealed the presence of significant amounts of the quinone of the neurotoxin 6-hydroxydopamine, together with some aminochrome and ill-defined melanin-like material. Quinone formation required the presence of iron, either in the ferrous or ferric form, and was unaffected by peroxidase, catalase, and hydroxyl radical scavengers, e.g. mannitol, as well as biologically relevant antioxidants, like ascorbate and glutathione. Hydrogen peroxide proved as effective as linoleic acid hydroperoxide in inducing dopamine oxidation and conversion to 6-hydroxydopamine quinone. Metal chelators, including EDTA and bipyridyl, markedly suppressed quinone formation without, however, inhibiting dopamine oxidation. These and other results are consistent with a hydroxyl radical independent hydroxylation/oxidation mechanism basically different from the Fenton reaction, which involves direct interaction of the peroxide with a dopamine-Fe(III) chelate generated during the process.

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

“…7). Iron is abundant in the SN and can react in a Fenton-type reaction with DA and hydrogen peroxide (produced extensively by monoamine oxidase during DA turnover) to produce 6-OHDA (43), which, in turn, can increase iron release from ferritin (35). This suggests that 6-OHDA may play an important role in perpetuating this damaging endogenous cycle.…”

Iron contributes to the formation of catechol isoquinolines and oxidative toxicity induced by overdose dopamine in dopaminergic SH-SY5Y cells

“…Both enzymatic and non-enzymatic catabolisms of dopamine are accelerated by the presence of redox active elements such as iron, zinc, or manganese [17] . The SNpc contains much higher concentration of iron than other brain regions, and it has been suggested that the increase in iron levels may catalyze the conversion of H 2 O 2 , which could be produced during the breakdown of dopamine, to highly reactive hydroxyl radicals, and thus resulted in increased oxidative damage in this region [18] .…”

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

“…Furthermore, the presence of 6-OHDA was seen to associate with increased activity of monoamine oxidase (MAO)-B, the enzyme bound to the outer mitochondrial membrane for catalyzing the oxidation of monoamines. It was shown that 6-OHDA is readily auto-oxidized and oxidatively deaminated by MAO, yielding hydrogen peroxide (H 2 O 2 ), which, in turn, generates hydroxyl radicals (-OH), the most reactive of these being ROS [17,18], as well as producing corresponding p-quinone. 6-OHDA quinine triggers a cascade of oxidative reactions, resulting in the formation of an insoluble polymeric pigment that is related to neuromelanin [19].…”