The neuromelanin of human substantia nigra and its interaction with metals

Zecca, Luigi; Tampellini, Davide; Gatti, Alberto; Crippa, Raimondo; Eisner, M.; Sulzer, David; Itô, Shôsuke; Fariello, Ruggero G.; Gallorini, M.

doi:10.1007/s007020200055

Cited by 87 publications

(62 citation statements)

References 43 publications

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“…In the SN of PD patients, redox-active iron levels are increased by 30 -35% compared with age-matched controls (for review, see Zecca et al, 2004;Götz et al, 2004). Neuromelanin, a dark pigment produced in catecholaminergic neurons of the human SN and locus ceruleus, acts as a storage system for iron in dopaminergic neurons (Zecca et al, 2002) and has been found to associate with large amounts of iron in diseased nigral tissue (Jellinger et al, 1992(Jellinger et al, , 1993. Neuromelanin could potentially serve a neuroprotective function by sequestering free intracellular iron.…”

Section: Resultsmentioning

confidence: 99%

Progressive Degeneration of Human Mesencephalic Neuron-Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway

Lotharius

Falsig²,

Beek³

et al. 2005

J. Neurosci.

225

240

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Models of Parkinson's disease (PD) based on selective neuronal death have been used to study pathogenic mechanisms underlying nigral cell death and in some instances to develop symptomatic therapies. For validation of putative neuroprotectants, a model is desirable in which the events leading to neurodegeneration replicate those occurring in the disease. We developed a human in vitro model of PD based on the assumption that dysregulated cytoplasmic dopamine levels trigger cell loss in this disorder. Differentiated human mesencephalic neuron-derived cells were exposed to methamphetamine (METH) to promote cytoplasmic dopamine accumulation. In the presence of elevated iron concentrations, as observed in PD, increased cytosolic dopamine led to oxidative stress, c-Jun N-terminal kinase (JNK) pathway activation, neurite degeneration, and eventually apoptosis. We examined the role of the mixed-lineage kinases (MLKs) in this complex degenerative cascade by using the potent inhibitor 3,9 -bis[(ethylthio)methyl]-K-252a (CEP1347). Inhibition of MLKs not only prevented FeCl2ϩ /METH-induced JNK activation and apoptosis but also early events such as neurite degeneration and oxidative stress. This broad neuroprotective action of CEP1347 was associated with increased expression of an oxidative stress-response modulator, activating transcription factor 4. As a functional consequence, transcription of the cystine/glutamate and glycine transporters, cellular cystine uptake and intracellular levels of the redox buffer glutathione were augmented. In conclusion, this new human model of parkinsonian neurodegeneration has the potential to yield new insights into neurorestorative therapeutics and suggests that enhancement of cytoprotective mechanisms, in addition to blockade of apoptosis, may be essential for disease modulation.

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Section: Resultsmentioning

confidence: 99%

Progressive Degeneration of Human Mesencephalic Neuron-Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway

Lotharius

Falsig²,

Beek³

et al. 2005

J. Neurosci.

225

240

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“…[84] Neuromelanin has been reported to have a dichotomous role (adverse or protective): beneficial when it reduces the oxidative stress in the brain due to its ability to bind cations; detrimental when it exacerbates the oxidative stress releasing H 2 O 2 or by reducing redox-active metals to a more reactive state. [85][86][87] Particular efforts have been made in understanding the binding of iron to neuromelanin, [76,[88][89][90][91][92][93][94][95] as iron was reported in dopaminergic neurons of Parkinsonian brains. [8] Recently, Sepia melanin has been identified as a suitable model to describe the binding characteristics of neuromelanin.…”

Section: Introductionmentioning

confidence: 99%

Natural melanin pigments and their interfaces with metal ions and oxides: emerging concepts and technologies

Mauro

Soliveri

et al. 2017

MRS Communications

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Melanin (from the Greek μέλας, mélas, black) is a biopigment ubiquitous in flora and fauna, featuring broadband optical absorption, hydration-dependent electrical response, ion-binding affinity as well as antioxidative and radical-scavenging properties. In the human body, photoprotection in the skin and ion flux regulation in the brain are some biofunctional roles played by melanin. Here we discuss the progress in melanin research that underpins emerging technologies in energy storage/conversion, ion separation/water treatment, sunscreens, and bioelectronics. The melanin research aims at developing approaches to explore natural materials, well beyond melanin, which might serve as a prototype benign material for sustainable technologies.

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“…However, these studies mainly concerned the ability of neuromelanin to bind iron, which may determine the risk of oxidative stress in the Substantia nigra and Locus coeruleus of the human brain (Kropf et al, 1998;Shima et al, 1997;Zecca et al, 2001Zecca et al, , 2002 or ion-exchange properties of Sepia melanin, which is probably not a very good model for human eumelanin Liu et al, 2004;Samokhvalov et al, 2004).…”

Section: Ion-exchange Propertiesmentioning

confidence: 99%

The physical and chemical properties of eumelanin

Meredith

Sarna

2006

Pigment Cell Research

885

1,045

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SummaryIn this article, we review the current state of knowledge concerning the physical and chemical properties of the eumelanin pigment. We examine properties related to its photoprotective functionality, and draw the crucial link between fundamental molecular structure and observable macroscopic behaviour. Where necessary, we also briefly review certain aspects of the pheomelanin literature to draw relevant comparison. A full understanding of melanin function, and indeed its role in retarding or promoting the disease state, can only be obtained through a full mapping of key structure-property relationships in the main pigment types. We are engaged in such an endeavor for the case of eumelanin.

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The neuromelanin of human substantia nigra and its interaction with metals

Cited by 87 publications

References 43 publications

Progressive Degeneration of Human Mesencephalic Neuron-Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway

Progressive Degeneration of Human Mesencephalic Neuron-Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway

Natural melanin pigments and their interfaces with metal ions and oxides: emerging concepts and technologies

The physical and chemical properties of eumelanin

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