espcrbulletin - European Society for Pigment Cell Research

Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin
and oxidative damage in the nigrostriatal system. Journal of Neurochemistry 95(1): 89-98,
2005.
Abstract : Oxidative stress is believed to contribute to the pathophysiol. of Parkinson's disease, in
which nigrostriatal dopaminergic (DA) neurons undergo degeneration. Identification of
endogenous mols. that contribute to generation of oxidative stress and vulnerability of these cells is
crit. in understanding the etiol. of this disease. Exposure to tetrahydrobiopterin (BH4), the
obligatory cofactor for DA synthesis, was obsd. previously to cause oxidative damage in DA cells.
To demonstrate the physiol. relevance of this observation, we investigated whether an overprodn.
of BH4 and DA might actually occur in vivo, and, if it did, whether this might lead to oxidative
damage to the nigrostriatal system. Immobilization stress (IMO) elevated BH4 and DA and their
synthesizing enzymes, tyrosine hydroxylase and GTP cyclohydrolase I. This was accompanied by
elevation of lipid peroxidn. and protein-bound quinone, and activities of antioxidant enzymes.
These increases in the indexes of oxidative stress appeared to be due to increased BH4 synthesis
because they were abolished following administration of the BH4 synthesis inhibitor, 2,4-diamino-
6-hydroxy-pyrimidine. IMO also caused accumulation of neuromelanin and degeneration of the
nigrostriatal system. These results demonstrate that a severe stress can increase BH4 and DA and
cause oxidative damages to the DA neurons in vivo, suggesting relevance to Parkinson's disease.
- Li, Jie; Scheller, Carsten; Koutsilieri, Eleni; Griffiths, Francine; Beart, Philip M.; Mercer, Linda
D.; Halliday, Glenda; Kettle, Emma; Rowe, Dominic; Riederer, Peter; Gerlach, Manfred;
Rodriguez, Michael; Double, Kay L.
Differential effects of human neuromelanin and synthetic dopamine melanin on neuronal and
glial cells. Journal of Neurochemistry 95(2): 599-608, 2005.
Abstract : We investigated the effects of neuromelanin (NM) isolated from the human substantia
nigra and synthetic dopamine melanin (DAM) on neuronal and glial cell lines and on primary rat
mesencephalic cultures. Lactate dehydrogenase (LDH) activity and lipid peroxidn. were
significantly increased in SK-N-SH cells by DAM but not by NM. In contrast, iron-satd. NM
significantly increased LDH activity in SK-N-SH cells, compared with 100 mg/mL ETDA-treated
NM contg. a low concn. of bound iron. DAM, but not NM, stimulated hydroxyl radical prodn. and
increased SK-N-SH cell death via apoptotic-like mechanisms. Neither DAM nor NM induced any
changes in the glial cell line U373. 3H-Dopamine uptake in primary rat mesencephalic cultures
was significantly reduced in DAM- compared with NM-treated cultures, accompanied by increased
cell death via an apoptosis-like mechanism. Interestingly, Fenton-induced cell death was
significantly decreased in cultures treated with both Fenton reagent and NM, an effect not seen in
cultures treated with Fenton reagent plus DAM. These data are suggestive of a protective role for
neuromelanin under conditions of high oxidative load. Our findings provide new evidence for a
physiol. role for neuromelanin in vivo and highlights the caution with which data based upon
model systems should be interpreted.
- Nicolaus, Bruno J. R.
A critical review of the function of neuromelanin and an attempt to provide a unified theory.
Medical Hypotheses 65(4): 791-796, 2005.
Abstract : This paper provides a crit. review of the numerous and various biol. functions so far
attributed to neuromelanin and an attempt to provide a unified theory based on the peculiar phys.
and chem. properties of the black particle (the neuromelanin cage). It is stressed that neuromelanin
is not homogeneous, as is commonly accepted, but is made up of different substrate specific black
pigments formed by the oxidn. of o.diphenols or other oxygenated precursors (substantia nigra
melanin, locus coeruleus melanin, retinal pigmented epithelium or ocular melanin, inner-ear
melanin, and so on). Ocular melanin is believed to protect the eye by trapping metals and free
radicals. The paper shows that this unconfirmed mechanism is a rather fortuitous irreversible mol.
accident, which at times may prove itself deleterious. Albinism often leads to deafness in animals,
indicating a genetic correlation. These two conditions appear to be correlated at a mol. level to
1427