Certain drugs with
melanin affinity are known to have caused pigmentary lesions in the eye and skin. This was the basis for the hypothesis that compounds with
melanin affinity may cause damage also in other
melanin-bearing tissues such as the substantia nigra. The heterogeneity of compounds that binds to
melanin is large. Toxins, drugs, and several other compounds have
melanin affinity. Compounds showing the highest affinity are mainly organic
amines and
metal ions. The binding of toxicants to
melanin probably protects the cells initially. However, the binding is normally, slowly reversible and
melanin may accumulate the toxicant and gradually release it into the cytosol. Several studies indicate that
neuromelanin may play a significant role both in the initiation and in the progression of neurodegeneration.
MPTP/MPP(+) that has been causally linked with
Parkinsonism has high affinity for
neuromelanin, and the induced dopaminergic
denervation correlates with the
neuromelanin content in the cells. This shows that the toxicological implications of the accumulation of toxicants in pigmented neurons and its possible role in neurodegeneration should not be neglected. Extracellular
neuromelanin has been reported to activate dendritic cells and microglia. An initial neuronal damage induced by a neurotoxicant that leaks
neuromelanin from the cells may therefore lead to a vicious cycle of
neuroinflammation and further neurodegeneration. Although there are many clues to the particular vulnerability of dopaminergic neurons of substantia nigra in
Parkinson's disease, the critical factors are not known. Further studies to determine the importance of
neuromelanin in neurodegeneration and
Parkinson's disease are warranted.