Abstract
Parkinson’s disease is associated with degeneration of neuromelanin (NM)-containing substantia nigra dopamine (DA) neurons and subsequent decreases in striatal DA transmission. Dopamine spontaneously forms a melanin through a process called melanogenesis. The present study examines conditions that promote/prevent DA melanogenesis. The kinetics, intermediates, and products of DA conversion to melanin in vitro, and DA melanogenesis under varying levels of Fe3+, pro-oxidants, and antioxidants were examined. The rate of melanogenesis for DA was substantially greater than related catecholamines norepinephrine and epinephrine and their precursor amino acids tyrosine and l-Dopa as measured by UV-IR spectrophotometry. Dopamine melanogenesis was concentration dependent on the pro-oxidant species and Fe3+. Melanogenesis was enhanced by the pro-oxidant hydrogen peroxide (EC50 = 500 μM) and decreased by the antioxidants ascorbate (IC50 = 10 μM) and glutathione (GSH; IC50 = 5 μM). Spectrophotometric results were corroborated by tuning a fast-scan cyclic voltammetry system to monitor DA melanogenesis. Evoked DA release in striatal brain slices resulted in NM formation that was prevented by GSH. These findings suggest that DA melanogenesis occurs spontaneously under physiologically-relevant conditions of oxidative stress and that NM may act as a marker of past exposure to oxidative stress.
Highlights
Melanin is a broad term for a group of natural pigments formed by the oxidation of amino acids or catecholamines followed by polymerization into an insoluble pigment
extracellular fluid (ECF) and ICF were used as buffers to mirror extracellular and intracellular conditions, the focus of this study was to monitor the chemical reaction of DA conversion to melanin within physiologic parameters, the role of metal ions in DA melanogenesis was evaluated at concentrations across their known cellular ranges
The results demonstrated that the rate of melanin formation was directly proportional to the initial concentration of DA in solution, with higher concentrations of DA resulting in faster rates of melanin formation
Summary
Melanin is a broad term for a group of natural pigments formed by the oxidation of amino acids or catecholamines followed by polymerization into an insoluble pigment. Neuromelanin is a brown to black melanin found in specific populations of catecholaminergic neurons in the brain, including noradrenergic neurons in the locus coeruleus (LC) and dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc) in the midbrain of humans and some non-human primates [6,8]. Given the emerging evidence that oxidative stress plays a large role in PD pathogenesis [14,15,16], NM may have a protective role This means that NM holds a repository of redox inactive iron and potentially other heavy metals; if spilled into the extracellular space (for example, due to apoptosis), NM can degrade resulting in a sudden release of toxic metals and inflammatory response [17]. While NM may have a neuroprotective role [18], it can lead to a cascade of DA cell death once one cell dies and releases its NM reservoirs [17]
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