Neuromelanin can protect against iron‐mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease

Abstract

In Parkinson’s disease (PD), dopamine neurons containing neuromelanin selectively degenerate. Neuromelanin binds iron and accumulates in aging. Iron accumulates in reactive form during aging, PD, and is involved in neurodegeneration. It is not clear how the interaction of neuromelanin and iron can be protective or toxic by modulating redox processes. Here, we investigated the interaction of neuromelanin from human substantia nigra with iron in the presence of ascorbic acid, dopamine, and hydrogen peroxide. We observed that neuromelanin blocks hydroxyl radical production by Fenton’s reaction, in a dose‐dependent manner. Neuromelanin also inhibited the iron‐mediated oxidation of ascorbic acid, thus sparing this major antioxidant molecule in brain. The protective effect of neuromelanin on ascorbate oxidation occurs even in conditions of iron overload into neuromelanin. The blockade of iron into a stable iron–neuromelanin complex prevents dopamine oxidation, inhibiting the formation of neurotoxic dopamine quinones. The above processes occur intraneuronally in aging and PD, thus showing that neuromelanin is neuroprotective. The iron–neuromelanin complex is completely decomposed by hydrogen peroxide and its degradation rate increases with the amount of iron bound to neuromelanin. This occurs in PD when extraneuronal iron–neuromelanin is phagocytosed by microglia and iron–neuromelanin degradation releases reactive/toxic iron.

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

“…These methods could be used to measure iron accumulations as well as target emerging therapeutic interventions (Adlard et al, 2008;Cahill et al, 2008;ChenRoetling et al, 2009;Hider et al, 2008;Mandel et al, 2008;Zecca et al, 2008) (for review see Kell, 2009) to high-risk groups identified by MRI, genetic, and clinical biomarkers, years before clinical manifestations of disease. Early intervention in higher-risk subgroups may make it possible to increase effectiveness of treatments, decrease the need for more-aggressive approaches at later stages, and may identify heretofore unexplored opportunities for primary prevention for the exponentially increasing burden of age-related neurodegenerative diseases (Bartzokis, 2009;Bartzokis et al, 2007c).…”

“…Treatment efforts to reduce the deleterious effects of brain iron accumulations in old age (Adlard et al, 2008;Cahill et al, 2008;Chen-Roetling et al, 2009;Hider et al, 2008;Mandel et al, 2008;Zecca et al, 2008) (for review see Kell, 2009) should take into consideration that large subgroups of the population may substantially differ in brain iron regulation mechanisms and thus differ in their response to such interventions.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Under normal physiological conditions, excess iron can be sequestrated in ferritin and neuromelanin, and in this respect neuromelanin has been described to be neuroprotective [103] Thus, elevated levels of iron observed in the SN of PD patients may reflect a dysfunction of brain iron homeostasis. Alternatively, the excess in iron content may be due to brain iron deposition associated with aging [104].…”

Iron, Aging, and Neurodegeneration

“…Neuromelanin is synthesized from L-Dopa in dopaminergic cells and forms stable complexes with Fe(III). Thus cells expressing neuromelanin are likely to have increased iron storage [21,22].…”